Showing papers by "Giuseppe Mancia published in 2020"

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19.

Abstract: Background A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covi...

Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake.

Abstract: Several blood pressure guidelines recommend low sodium intake ( 5 g/day, while awaiting the results of large randomized controlled trials of sodium reduction on incidence of cardiovascular events and mortality.

COVID-19 and arterial hypertension: Hypothesis or evidence?

Abstract: Investigations reported that hypertension, diabetes, and cardiovascular diseases were the most prevalent comorbidities among the patients with coronavirus disease 2019 (COVID-19). Hypertension appeared consistently as the most prevalent risk factors in COVID-19 patients. Some investigations speculated about the association between renin-angiotensin-aldosterone system (RAAS) and susceptibility to COVID-19, as well as the relationship between RAAS inhibitors and increased mortality in these patients. This raised concern about the potential association between hypertension (and its treatment) and propensity for COVID-19. There are only a few follow-up studies that investigated the impact of comorbidities on outcome in these patients with conflicting findings. Hypertension has been proven to be more prevalent in patients with an adverse outcome (admission in intensive care unit, use of mechanical ventilation, or death). So far, there is no study that demonstrated independent predictive value of hypertension on mortality in COVID-19 patients. There are many speculations about this coronavirus and its relation with different risk factors and underlying diseases. The aim of this review was to summarize the current knowledge about the relationship between hypertension and COVID-19 and the role of hypertension on outcome in these patients.

Limited reproducibility of MUCH and WUCH: evidence from the ELSA study

Abstract: Aims To evaluate the long-term reproducibility of masked (MUCH) and white-coat uncontrolled hypertension (WUCH), an information crucial for determining the long-term prognostic impact of these conditions. Methods and results Reproducibility of MUCH and WUCH was assessed in 1664 hypertensive patients recruited for the European Lacidipine Study on Atherosclerosis and treated with atenolol or lacidipine (±additional drugs) during a 4-year period. Office and 24 h blood pressure (BP) was measured at baseline and every year during treatment, allowing repeated classification of either condition. After 1 year of treatment 21.1% and 17.8% of the patients were classified as MUCH and WUCH, respectively. For both conditions the prevalence was similar in the following years, although with a large change in patients composition because only about 1/3 of patients classified as MUCH or WUCH at one set of office and ambulatory BP measurements maintained the same classification at a subsequent set of measurements. In only 4.5% and 6.2% MUCH and WUCH persisted throughout the treatment period. MUCH and WUCH reproducibility was worse than that of patients showing control or lack of control of both office and ambulatory BP, i.e. controlled and uncontrolled hypertension, respectively. Conclusion Both MUCH and WUCH display poor reproducibility over time. This should be taken into account in studies assessing the long-term prognostic value of these conditions based on only one set of BP measurements.

Review and meta-analysis of renal artery damage following percutaneous renal denervation with radiofrequency renal artery ablation.

Abstract: Aims We aimed to estimate the rate of renal artery adverse events following renal denervation with the most commonly applied radiofrequency catheter system based on a comprehensive review of published reports. Methods and results We reviewed 50 published renal denervation (RDN) trials reporting on procedural safety including 5,769 subjects with 10,249 patient-years of follow-up. Twenty-six patients with renal artery stenosis or dissection (0.45%) were identified of whom 24 (0.41%) required renal artery stenting. The primary meta-analysis of all reports indicated a 0.20% pooled annual incidence rate of stent implantation (95% CI: 0.12 to 0.29% per year). Additional sensitivity analyses yielded consistent pooled estimates (range: 0.17 to 0.42% per year). Median time from RDN procedure to all renal intervention was 5.5 months (range: 0 to 33 months); 79% of all events occurred within one year of the procedure. A separate review of 14 clinical trials reporting on prospective follow-up imaging using either magnetic resonance imaging, computed tomography or angiography following RDN in 511 total subjects identified just 1 new significant stenosis (0.20%) after a median of 11 months post procedure (one to 36 months). Conclusions Renal artery reintervention following renal denervation with the most commonly applied RF renal denervation system (Symplicity) is rare. Most events were identified within one year.

Does Estimated Pulse Wave Velocity Add Prognostic Information? : MORGAM Prospective Cohort Project

Abstract: The Reference Values for Arterial Stiffness Collaboration has derived an equation using age and mean blood pressure to estimated pulse wave velocity (ePWV), which predicted cardiovascular events independently of Systematic COoronary Risk Evaluation (SCORE) and Framingham Risk Score. The study aim was to investigate the independent association between ePWV and clinical outcomes in 107 599 apparently healthy subjects (53% men) aged 19 to 97 years from the MORGAM Project who were included between 1982 and 2002 in 38 cohorts from 11 countries. Using multiple Cox-regression analyses, the predictive value of ePWV was calculated adjusting for country of inclusion and either SCORE, Framingham Risk Score, or traditional cardiovascular risk factors (age, sex, smoking, systolic blood pressure, body mass index [BMI], total and high-density lipoprotein cholesterol). Cardiovascular mortality consisted of fatal stroke, fatal myocardial infarction, or coronary death, and the composite cardiovascular end point consisted of stroke, myocardial infarction, or coronary death. Model discrimination was assessed using Harrell's C-statistic. Adjusting for country and logSCORE or Framingham Risk Score, ePWV was associated with all-cause mortality (hazard ratio, 1.23 [95% CI 1.20-1.25] per m/s or 1.32 [1.29-1.34]), cardiovascular mortality (1.26 [1.21-1.32] or 1.35 [1.31-1.40]), and composite cardiovascular end point (1.19 [1.16-1.22] or 1.23 [1.20-1.25]; all P<0.001). However, after adjusting for traditional cardiovascular risk factors, ePWV was only associated with all-cause mortality (1.15 [1.08-1.22], P<0.001) and not with cardiovascular mortality (0.97 [0.91-1.03]) nor composite cardiovascular end point (1.10 [0.97-1.26]). The areas under the last 3 receiver operator characteristic curves remained unchanged when adding ePWV. Elevated ePWV was associated with subsequent mortality and cardiovascular morbidity independently of systematic coronary risk evaluation and Framingham Risk Score but not independently of traditional cardiovascular risk factors.

Association Between the European Society of Cardiology/European Society of Hypertension Heart Rate Thresholds for Cardiovascular Risk and Neuroadrenergic Markers.

Abstract: The recent European Society of Cardiology/European Society of Hypertension hypertension guidelines identify resting heart rate (HR) values >80 bpm as predictors of cardiovascular risk, with the unproven assumption that this might reflect the presence of a sympathetic overdrive In the present study, we tested this hypothesis throughout the use of direct and indirect sympathetic markers In 193 untreated moderate essential hypertensives aged 504±06 years (mean±SEM), we measured clinic and ambulatory blood pressure and corresponding HR, venous plasma norepinephrine (high performance liquid chromatography), and muscle sympathetic nerve traffic (microneurography) We then subdivided the study population into 2 groups according to HR 80 bpm Eighty-four patients displayed resting HR >80 bpm, which was this cutoff value in the remaining 109 patients, the 2 groups showing superimposable age, and sex distribution Clinic and ambulatory blood pressure were similar in the 2 groups, whereas left ventricular mass index was significantly greater in the group with HR >80 bpm Muscle sympathetic nerve traffic values were also significantly greater in this latter group (7277±09 versus vs 3683±13 bursts/min, P 80 bpm are characterized by a marked sympathetic overdrive, particularly when direct adrenergic markers are used This finding suggests that cardiac and peripheral sympathetic activation are involved in the increased cardiovascular risk detected in this group of patients

Resting heart rate and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk analysis from the ONTARGET/TRANSCEND trials.

Abstract: AIMS Resting heart rate (RHR) has been shown to be associated with cardiovascular outcomes in various conditions. It is unknown whether different levels of RHR and different associations with cardiovascular outcomes occur in patients with or without diabetes, because the impact of autonomic neuropathy on vascular vulnerability might be stronger in diabetes. METHODS AND RESULTS We examined 30 937 patients aged 55 years or older with a history of or at high risk for cardiovascular disease and after myocardial infarction, stroke, or with proven peripheral vascular disease from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination followed for a median of 56 months. We analysed the association of mean achieved RHR on-treatment with the primary composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, the components of the composite primary outcome, and all-cause death as continuous and categorical variables. Data were analysed by Cox regression analysis, ANOVA, and χ2 test. These trials were registered with ClinicalTrials.gov.number NCT00153101. Patients were recruited from 733 centres in 40 countries between 1 December 2001 and 31 July 2008 (ONTARGET) and 1 November 2001 until 30 May 2004 (TRANSCEND). In total, 19 450 patients without diabetes and 11 487 patients with diabetes were stratified by mean RHR. Patients with diabetes compared to no diabetes had higher RHRs (71.8 ± 9.0 vs. 67.9 ± 8.8, P < 0.0001). In the categories of <60 bpm, 60 ≤ 65 bpm, 65 ≤ 70 bpm, 70 ≤ 75 bpm, 75 ≤ 80 bpm and ≥80 bpm, non-diabetic patients had an increased hazard of the primary outcome with mean RHR of 75 ≤ 80 bpm (adjusted hazard ratio [HR] 1.17 (1.01-1.36)) compared to RHR 60 ≤ 65 bpm. For patients with in-trial RHR ≥80 bpm the hazard ratios were highest (diabetes: 1.96 (1.64-2.34), no diabetes: 1.73 (1.49-2.00), For cardiovascular death hazards were also clearly increased at RHR ≥80 bpm (diabetes [1.99, (1.53-2.58)], no diabetes [1.73 (1.38-2.16)]. Similar results were obtained for hospitalization for heart failure and all-cause death while the effect of RHR on myocardial infarction and stroke was less pronounced. Results were robust after adjusting for various risk indicators including beta-blocker use and atrial fibrillation. No significant association to harm was observed at lower RHR. CONCLUSION Mean RHR above 75-80 b.p.m. was associated with increased risk for cardiovascular outcomes except for stroke. Since in diabetes, high RHR is associated with higher absolute event numbers and patients have higher RHRs, this association might be of particular clinical importance in diabetes. These data suggest that RHR lowering in patients with RHRs above 75-80 b.p.m. needs to be studied in prospective trials to determine if it will reduce outcomes in diabetic and non-diabetic patients at high cardiovascular risk. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov.Unique identifier: NCT00153101.

Sex differences in the adherence of antihypertensive drugs: a systematic review with meta-analyses

Abstract: Objectives Poor worldwide rate of blood pressure control is largely due to poor adherence to antihypertensive (AHT) drug treatment. The question of whether sex affects adherence has long been debated but conflicting findings have been reported on this issue. Our objective was to evaluate sex differences in the adherence to AHT therapy. Research design and methods Studies were identified through a systematic search of PubMed, CINAHL, PsycINFO, Web of Science and Google Scholar (through January 2020) and manual handsearching of relevant articles. Observational studies reporting adherence to AHT drugs measured by self-report or pharmacy refill prescription-based methods among men and women were included. Summarised estimates of ORs with 95% CIs were calculated using random-effects model and meta-regression models. Results From 12 849 potentially relevant publications, 82 studies (15 517 457 men and 18 537 599 women) were included. No significant between-sex differences in adherence to AHT were observed, whether all study-specific estimates were summarised (ORs 1.04, 95% CI 1.00 to 1.09, p=0.07), nor estimates were pooled according to the method for measuring adherence. Among patients aged 65 years or older, lower self-reported adherence was observed in women (ORs 0.84, 95% CI 0.72 to 0.97, p=0.02), while the main result remained unchanged according to other subgroup analyses. Conclusions Definitive evidence of sex differences in adherence to AHT therapy cannot be drawn. Our little knowledge about factors affecting adherence, in particular of sex effect among elderly, urgently requires high-quality studies investigating these issues.

Update of the position paper on arterial hypertension and erectile dysfunction.

Abstract: Sexual health is an integral part of overall health, and an active and healthy sexual life is an essential aspect of a good life quality. Cardiovascular disease and sexual health share common risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, obesity, and smoking) and common mediating mechanisms (endothelial dysfunction, subclinical inflammation, and atherosclerosis). This generated a shift of thinking about the pathophysiology and subsequently the management of sexual dysfunction. The introduction of phosphodiesterase type 5 inhibitors revolutionized the management of sexual dysfunction in men. This article will focus on erectile dysfunction and its association with arterial hypertension. This update of the position paper was created by the Working Group on Sexual Dysfunction and Arterial Hypertension of the European Society of Hypertension. This working group has been very active during the last years in promoting the familiarization of hypertension specialists and related physicians with erectile dysfunction, through numerous lectures in national and international meetings, a position paper, newsletters, guidelines, and a book specifically addressing erectile dysfunction in hypertensive patients. It was noted that erectile dysfunction precedes the development of coronary artery disease. The artery size hypothesis has been proposed as a potential explanation for this observation. This hypothesis seeks to explain the differing manifestation of the same vascular condition, based on the size of the vessels. Clinical presentations of the atherosclerotic and/or endothelium disease in the penile arteries might precede the corresponding manifestations from larger arteries. Treated hypertensive patients are more likely to have sexual dysfunction compared with untreated ones, suggesting a detrimental role of antihypertensive treatment on erectile function. The occurrence of erectile dysfunction seems to be related to undesirable effects of antihypertensive drugs on the penile tissue. Available information points toward divergent effects of antihypertensive drugs on erectile function, with diuretics and beta-blockers possessing the worst profile and angiotensin receptor blockers and nebivolol the best profile.

Beta-blockers in hypertension: overview and meta-analysis of randomized outcome trials

Abstract: Background Meta-analyses from randomized outcome-based trials have challenged the role of beta-blockers for the treatment of hypertension. However, because they often include trials on diseases other than hypertension, the role of these drugs in the choice of the blood pressure (BP)-lowering treatment strategies remains unclear. Methods Electronic databases were searched for randomized trials that compared beta-blockers vs. placebo/no-treatment/less-intense treatment (BP-lowering trials) or beta-blockers vs. other antihypertensive agents in patients with or without hypertension (comparison trials). Among BP-lowering trials and according to baseline comorbidity, we separately considered trials in hypertension, trials without chronic heart failure or acute myocardial infarction, and trials with either chronic heart failure or acute myocardial infarction. Seven fatal and nonfatal outcomes were calculated (random-effects model) for BP-lowering or comparison trials. Results A total of 84 BP-lowering or comparison trials (165 850 patients) were eligible. In 67 BP-lowering trials (68 478 patients; mean follow-up 2.5 years; baseline SBP/DBP, 136/82 mmHg), beta blockers were associated with a lower incidence of major cardiovascular events [risk ratio 0.85 and 95% confidence interval (95% CI) 0.78-0.92] and all-cause death (risk ratio 0.81 and 95% CI 0.75-0.86). Restriction of the analysis to five trials recruiting exclusively hypertensive patients (18 724 patients; mean follow-up 5.1 years; baseline SBP/DBP 163/94 mmHg), a -10.5/-7.0 mmHg BP decrease was accompanied by reduction of major cardiovascular events by 22% (95% CI, 6-34). In 24 comparison trials (103 764 patients, 3.92 years of mean follow-up), beta-blockers compared with other agents were less protective for stroke and all-cause death in all trials and in trials conducted exclusively in hypertensive patients (averaged risk ratio increase 20 and 6%, respectively, for both cases). Conclusion Compared with other antihypertensive agents, beta-blockers appear to be substantially less protective against stroke and overall mortality. However, they exhibit a substantial risk-reducing ability for all events when prescribed to lower BP in patients with modest or more clear BP elevations, and therefore can be used as additional agents in hypertensive patients.

Circadian variations in blood pressure and their implications for the administration of antihypertensive drugs: is dosing in the evening better than in the morning?

Abstract: Blood pressure (BP) follows a circadian rhythm with a physiological decrease during the night. Studies have demonstrated that nocturnal BP as well as its dipping pattern during night-time have a significant prognostic importance for mortality and the occurrence of cardiovascular events. Therefore, hypertension management guidelines recommend to ascertain that patients treated for hypertension have well controlled BP values around the clock. To improve hypertension control during the night and eventually further reduce cardiovascular events, it has been proposed by some to prescribe at least one antihypertensive medication at bedtime. In this review, we have examined the data which could support the benefits of prescribing BP-lowering drugs at bedtime. Our conclusion is that there is no convincing evidence that the administration of BP-lowering drugs in the evening provides any significant advantage in terms of quality of BP control, prevention of target organ damage or reduction of cardiovascular events. Before changing practice for unproven benefits, it would be wise to wait for the results of the ongoing trials that are addressing this issue.

Sympathetic neural abnormalities in type 1 and type 2 diabetes: a systematic review and meta-analysis.

Abstract: BACKGROUND Microneurographic recordings of muscle sympathetic nerve activity (MSNA) have shown that sympathetic activation may characterize diabetes mellitus. However, it is recognized that comorbidities and metabolic abnormalities frequently associated with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) diabetes affect MSNA, generating potential confounding effects and making the association between sympathetic activation and diabetes mellitus still a controversial matter. METHODS The present meta-analysis evaluated 11 microneurographic studies enrolling 314 diabetes mellitus patients and healthy controls, and MSNA was chosen as the main variable of interest. Collection of the data included indirect adrenergic markers such as heart rate and venous plasma noradrenaline, together with hemodynamic, anthropometric and metabolic variables. RESULTS A total of 11 microneurographic studies were evaluated including 314 diabetes mellitus patients and controls. Diabetes mellitus displayed MSNA significantly greater than controls (mean difference amounting to 8.1, 95% confidence interval 1.21-15.08, P < 0.05). This difference was ascribed to T2DM, since T1DM patients displayed MSNA values superimposable to controls. In T2DM MSNA was directly related to age (r = 0.83, β = 0.82, P < 0.04) and plasma insulin (r = 1.00, β = 2.25, P < 0.01) but not to other variables. CONCLUSION T2DM-related sympathetic activation is detectable even when obesity, hypertension and metabolic syndrome are excluded; not found in T1DM; not associated with anthropometric and hemodynamic variables; and related to plasma insulin.

Sympathetic overdrive in the metabolic syndrome: meta-analysis of published studies.

Abstract: OBJECTIVE The microneurographic technique has shown that sympathetic overactivity may characterize patients with the metabolic syndrome. However, technical and methodological limitations of the studies prevented to draw definite conclusions. The present meta-analysis evaluated 16 microneurographic studies including 650 individuals, 444 metabolic syndrome patients and 206 healthy controls, respectively. The analysis was primarily based on muscle sympathetic nerve traffic (MSNA) quantified by microneurography in metabolic syndrome. METHODS Assessment was extended to the relationships of MSNA with an indirect neuroadrenergic marker, such as heart rate (HR), anthropometric variables, as BMI, waist-hip ratio and metabolic profile. RESULTS Metabolic syndrome individuals displayed MSNA values (means ± SEM) significantly greater than controls (58.6 ± 4.8 versus 41.6 ± 4.1 bursts/100 heart beats, P < 0.01). This result was independent on the concomitant presence of sleep apnea and drug treatment. MSNA was directly and significantly related to clinic SBP (r = 0.91, P < 0.01) but not to BMI (r = 0.17, P = NS), whereas no significant relationship was found between MSNA and metabolic variables included in the definition of metabolic syndrome. No significant correlation was found between MSNA and HR. CONCLUSION These data provide evidence that metabolic syndrome is characterized by a marked increase (about 30%) in MSNA. They also show that among the variables included in metabolic syndrome definition and related to the sympathetic overdrive blood pressure appears to be the most important one, at variance from what described in obesity in which metabolic and anthropometric factors play a major role. Finally in metabolic syndrome HR does not appear to represent a faithful mirror of the occurring sympathetic activation.

Isolated Nocturnal Hypertension: What Do We Know and What Can We Do?

Abstract: Nocturnal hypertension has been recognized as a significant risk factor for cardio- and cerebrovascular diseases. Blood pressure (BP) monitoring significantly increased our awareness of nocturnal hypertension and studies revealed its influence on target organ damage. Nocturnal hypertension is associated with nonphysiological 24-h BP patterns, which consider inadequate drop or even increment of nighttime BP in comparison with daytime BP (nondipping and reverse dipping). Nevertheless, investigations showed that nocturnal hypertension was a predictor of adverse outcome independently of circadian BP pattern. There are still many uncertainties regarding diagnosis, mechanisms and treatment of nocturnal hypertension. There is a small difference between American and European guidelines in cutoff values defining nocturnal hypertension. Pathophysiology is also not clear because many conditions such as diabetes, metabolic syndrome, obesity, sleep apnea syndrome, and renal diseases are related to nocturnal hypertension and nonphysiological circadian BP pattern, but mechanisms of nocturnal hypertension still remain speculative. Therapeutic approach is another important issue and chronotherapy provided the best results so far. There are studies which showed that some groups of antihypertensive medications are more effective in regulation of nocturnal BP, but it seems that the timing of drug administration has a crucial role in the reduction of nighttime BP and conversion of circadian patterns from nonphysiologic to physiologic. Follow-up studies are necessary to define clinical benefits of nocturnal BP reduction and restoring unfavorable 24-h BP variations to physiological variant.

The association between 24-h blood pressure patterns and left ventricular mechanics.

Abstract: Objective We sought to investigate left ventricular (LV) mechanics in the recently diagnosed hypertensive patients with different 24-h blood pressure (BP) patterns (dipping, nondipping, extreme dipping and reverse dipping). Methods The current cross-sectional study included 209 hypertensive patients who underwent 24-h ambulatory BP monitoring and comprehensive two-dimensional echocardiographic examination including multilayer strain analysis. Results There was no difference in 24-h and daytime BP values between four groups. Night-time BP significantly and gradually increased from extreme dippers, across dippers and nondippers, to reverse dippers. LV global longitudinal and circumferential strains were greater in dippers and extreme dippers than in nondippers and reverse dippers. This was also found for endocardial and epicardial LV longitudinal and circumferential strains. Multivariate logistic regression analysis demonstrated that nondipping and reverse dipping patterns were associated with reduced LV longitudinal strain [odds ratio (OR) 1.71 (95% confidence interval (CI): 1.10-5.61) and OR 2.50 (95% CI: 1.31-6.82), respectively] independently of age, sex, 24-h SBP, LV mass index and E/e. Only the reverse dipping BP pattern was independently of clinical and echocardiographic parameters related with reduced LV circumferential strain [OR 1.90 (95% CI: 1.10-4.80)]. Conclusion Nondipping and reverse dipping BP patterns had stronger impact on LV mechanics compared with patients with dipping and extreme dipping BP patterns in hypertensive population. LV functional and mechanical remodeling deteriorated from extreme dippers and dippers, to nondippers and reverse dippers.

Antihypertensive Treatment in Elderly Frail Patients: Evidence From a Large Italian Database.

Abstract: Aim of our study was to assess the relationship between adherence with antihypertensive drugs and the risk of death in frail versus nonfrail old individuals. Using the database of the Lombardy Region (Italy), we identified 1 283 602 residents aged ≥65 years (mean age 76) who had ≥3 prescriptions of antihypertensive drugs between 2011 and 2012. A nested case-control design was applied, with cases being the cohort members who died during the observation period (7 years). Logistic regression was used to model the association of interest, with adjustment for potential confounders. Adherence was measured by the proportion of the follow-up covered by prescriptions, and the analysis was separately performed in patients with a good, medium, poor, and very poor clinical status, as assessed by a score that has been shown to be a sensitive predictor of death in the Italian population. The 7-year death probability increased from 16% (good) to 64% (very poor) clinical status. Compared with patients with very low adherence with antihypertensive treatment ( 75% of time covered by prescriptions) exhibited a lower risk of all-cause mortality in each group, the difference decreasing progressively (-44%, -43%, -40%, and -33%) from the good to the very poor clinical status. Adherence with antihypertensive drug treatment was also associated with a lower risk of cardiovascular mortality. Adherence with antihypertensive appears to be protective in frail old patients, but the benefit is less marked than in patients with a good clinical status.

Hypertension in aortic stenosis: a focused review and recommendations for clinical practice.

Abstract: In patients with aortic stenosis, the presence of hypertension negatively affects the hemodynamic severity of the stenosis, and worsens adverse left ventricular remodeling. It accelerates the progression of the stenosis and is associated with worse prognosis. Proper management of hypertension is thus crucial but there are concerns about the safety and efficacy of antihypertensive medications as well as uncertainty about optimal blood pressure (BP) targets and their impact on left ventricular mass regression and survival benefits. In the present review, we discuss these issues based on the evidence available in the current literature. Focus is first directed on the consequences of a persistently elevated BP before and after surgical aortic valve replacement or transcatheter valve implantation, and the clinical significance of an abnormal BP response during exercise in patients with significant aortic stenosis. Available data on use of antihypertensive drugs are then critically addressed, the conclusion being that calcium channel blockers may be associated with lower survival, and that diuretics may have disadvantages in patients with left ventricular hypertrophy and smaller left ventricular cavity dimensions, β-blockers may be well tolerated and a better choice for patients with concomitant coronary artery disease and arrhythmias. Renin--angiotensin system blockers improve survival given either before or after valve intervention. Emphasis is placed on the fact that evidence is not derived from randomized trials but only from observational studies. Finally, we discuss the optimal SBP level to reach in patients with aortic stenosis. Again, randomized trials are not available but observational evidence suggests that values between 130 and 139 mmHg systolic and 70-90 mmHg diastolic might represent the best option, and lower BP targets should probably be avoided.

Heart failure and renal outcomes according to baseline and achieved blood pressure in patients with type 2 diabetes: results from EMPA-REG OUTCOME.

Abstract: BACKGROUND The sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin reduced cardiovascular death or heart failure hospitalizations in type 2 diabetes (T2D) in addition to a reduction of SBP. As heart failure patients often present with low SBP, which can challenge treatment initiation, we explored if empagliflozin's effect on SBP was independent of baseline SBP and heart failure status, and if the effect on cardiovascular and heart failure outcomes was influenced by updated mean SBP or by an early change in SBP after drug initiation. METHODS AND RESULTS A total of 7020 patients were treated with empagliflozin 10 mg, 25 mg or placebo and followed for a median of 3.1 years. All of them had BP measurement at baseline. We evaluated changes in SBP in the context of heart failure status at baseline and according to baseline SBP categories (<120, 120--<130, 130--<140, 140--<160, ≥160 mmHg). The updated mean SBP during the trial was calculated as a time-dependent variable. We then assessed the association of baseline and updated mean SBP with three-point major adverse cardiovascular events (3P-MACE), hospitalization for heart failure, cardiovascular death, hospitalization for heart failure or cardiovascular death, all-cause death, and incident/worsening nephropathy, and whether treatment effect of empagliflozin vs. placebo on these outcomes differed if adjusted for updated mean SBP. Finally, we evaluated the impact of early decline in SBP (≥5 mmHg at week 4) on the treatment effect of empagliflozin vs. placebo on these outcomes. Analyses were performed via Cox regression adjusting for baseline risk factors including a term for treatment subgroup interaction, and by landmark analyses starting at week 4. The difference in SBP reduction at week 12 between empagliflozin and placebo was 3--5 mmHg and similar regardless of baseline SBP category or HF status at baseline. Baseline SBP and updated mean SBP categories showed no association with cardiovascular outcomes, but was associated with new/worsening nephropathy. The treatment effects of empagliflozin on all explored outcomes were independent of updated mean SBP as well of the early drop in SBP on treatment. CONCLUSION In addition to decreasing SBP, empagliflozin reduced cardiovascular, heart failure and renal outcomes independently of updated mean SBP during the trial, and of the early SBP drop. These results suggest a BP-independent effect of empagliflozin on cardiovascular and heart failure outcomes. CLINICALTRIALS. GOV IDENTIFIER NCT01131676.

Diabetic cardiomyopathy: How can cardiac magnetic resonance help?

Abstract: Diabetes cardiomyopathy is a specific form of cardiac disease characteristic for diabetic patients. Development of echocardiography enabled diagnosis of diabetic cardiomyopathy significantly before the occurrence of heart failure. Previously was believed that left ventricular (LV) diastolic dysfunction represents the first detectable stage of diabetic cardiomyopathy. However, speckle tracking imaging and strain evaluation showed that mechanical changes occur before LV diastolic dysfunction. Nevertheless, it seems that the first detectable stage of diabetic cardiomyopathy is myocardial interstitial fibrosis, which currently could be diagnosed predominantly by cardiac magnetic resonance. T1 mapping evaluation before and after contrast injection enables assessment of extracellular volume (ECV) and provides qualitative and quantitative assessment of interstitial myocardial fibrosis in diabetic patients. Studies showed a strong correlation between ECV-parameter of interstitial fibrosis and level of glycated hemoglobin-main parameter of glucose control in diabetes. This stage of fibrosis is still not LV hypertrophy and it is reversible, which is of a great importance because of timely initiation of treatment. The necessity for early diagnose is significantly increasing due to the fact that diabetes and arterial hypertension are concomitant disorders in the large number of diabetic patients and it has been known that the risk of interstitial myocardial fibrosis is multiplied in patients with both conditions. Future follow-up investigations are essential to determine the causal relationship between interstitial fibrosis and outcome in these patients. The aim of this review was to summarize the current knowledge and clinical usefulness of CMR in diabetic patients.

Obstructive sleep apnoea syndrome and left ventricular hypertrophy: a meta-analysis of echocardiographic studies.

Abstract: AIM We investigated the association between obstructive sleep apnoea (OSA) and subclinical cardiac organ damage through a meta-analysis of echocardiographic studies that provided data on left ventricular hypertrophy (LVH), assessed as a categorical or continuous variable. DESIGN The PubMed, OVID-MEDLINE, and Cochrane library databases were systematically analyzed to search English-language articles published from 1 January 2000 to 15 August 2019. Studies were detected by using the following terms: 'obstructive sleep apnea', 'sleep quality', 'sleep disordered breathing', 'cardiac damage', 'left ventricular mass', 'left ventricular hypertrophy', and 'echocardiography'. RESULTS Meta-analysis included 5550 patients with OSA and 2329 non-OSA controls from 39 studies. The prevalence of LVH in the pooled OSA population was 45% (CI 35--55%). Meta-analysis of studies comparing the prevalence of LVH in participants with OSA and controls showed that OSA was associated with an increased risk of LVH (OR = 1.70, CI 1.44-2.00, P < 0.001). LV mass was significantly increased in patients with severe OSA as compared with controls (SMD 0.46 ± 0.08, CI 0.29-0.62, P < 0.001) or with mild OSA. This was not the case for studies comparing patients with unselected or predominantly mild OSA and controls (0.33 ± 0.17, CI -0.01 to 0.67, P = 0.057). CONCLUSION The present meta-analysis expands previous information on the relationship between OSA and echocardiographic LVH, so far based on individual studies. The overall evidence strongly suggests that the likelihood of LVH increases with the severity of OSA, thus exhibiting a continuous relationship.

Disregard the reported data from the HYGIA project: blood pressure medication not to be routinely dosed at bedtime.

Abstract: W e continuebeing concernedby the study ‘Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial’ which was published in the European Heart Journal [1]. The protocol article [2] suggested to us that no properly randomized controlled trial (RCT) with 19 084 participating patients had been performed. The database appears as a summary database of multiple smaller studies already completed and published, such as the MAPEC study [3], which included 2156 hypertensive patients in an identical protocol. There is no evidence that the strict rules that apply to RCTs were followed, no indicationof how the conduct of the study was monitored and no documentation of the membership of the event adjudication committee or of audit by independent investigators. According to the initial protocol (ClinicalTrials.gov NCT00741585) the authors engaged 20 centers but increased to 40 centers and 292 physicians doing yearly 48-h ambulatory blood pressure measurements (ABPM) on 19 000 patients. On this background, only 800 patients dropped out because of inappropriate 48-h measurements; this is impossible if one takes into account the known difficulties when using ABPM devices. Moreover, ABPMs were made with Spacelabs instruments that barely last 48 h in clinical use even when rechargeable batteries were used. Performing 48-h measurements on more than 19 000 patients annually would result in an enormous battery consumption. In total, the HYGIA study should have produced over 150 000 long-term blood pressure (BP) measurements with a failure rate of less than 10%; which we cannot achieve in clinical use, not even with Spacelabs devices.

Sympathetic Overactivation in Patients With Essential Hypertension and Hepatic Iron Overload.

Abstract: Iron overload has been recently shown to be associated with a hyperadrenergic state in genetic hemochromatosis. Whether this is also the case in essential hypertension, characterized by sympathetic activation and frequently by body iron overload, is unknown. In 17 healthy normotensive controls (age 52.3±3.2 years, mean±SE), in 21 age-matched patients with hypertension with iron overload (HT+), defined by serum ferritin levels, and in 28 hypertensives without this condition, we measured efferent postganglionic muscle sympathetic nerve traffic (microneurography), heart rate and blood pressure variability (power spectral analysis), serum ferritin, and metabolic variables. Muscle sympathetic nerve traffic was significantly (P<0.02 at least) greater in HT+ than in patients with hypertension without iron overload and normotensive subjects both when expressed as bursts incidence over time (41.8±1.4 versus 31.5±1.4 and 23.6±0.9 bursts/min) and as bursts corrected for heart rate (55.3±1.8 versus 42.3±1.2 and 31.7±1.2 bursts/100 heartbeats). In HT+, low-frequency systolic blood pressure variability was significantly reduced. In HT+, but not in the other 2 groups, muscle sympathetic nerve traffic was significantly related to serum ferritin (r=0.51, P<0.03), transferrin saturation (r=0.47, P<0.03), and hepatic iron load (r=0.76, P<0.0001, magnetic resonance imaging), as well as to homeostatic model assessment index values (r=0.46, P<0.05). These data provide the first evidence that in HT+ elevated serum ferritin is associated with a hyperadrenergic state of greater magnitude than the one seen in patients with hypertension without iron overload. They also show that the potentiation of the sympathetic activation detected in HT+ is related to elevated serum ferritin and to the associated metabolic alterations, possibly participating in the increased cardiovascular risk characterizing iron overload.

COVID-19, hypertension, and RAAS blockers: the BRACE-CORONA trial

Abstract: At the beginning of the COVID-19 pandemic, the hypertension world was shaken by the evidence that, as shown in 2003 for the severe acute respiratory syndrome (SARS)-corona virus, the SARS coronavirus-2 (SARS-CoV-2) virus entered the cell via an enzyme, the angiotensinconverting enzyme 2 (ACE2), which is part of the renin–angiotensin–aldosterone system (RAAS) and thus, albeit somewhat collaterally, of the mechanisms through which ACE-inhibitors, angiotensin receptor blockers and, to a lesser extent, mineralocorticoid receptor antagonists exert their therapeutic lifesaving influence in hypertension, heart failure, chronic kidney disease, and the post-myocardial infarction state. Evidence that these drugs might up-regulate ACE2 in several organs, including the lungs and the heart, favoured the hypothesis, widely reported by the press, that the susceptibility to the infection, as well as its severity, might increase by their chronic use, and that thus their discontinuation might represent an appropriate defense measure against the expanding rate of the disease and its lethality. Large observational studies performed in the subsequent months have made the hypothesis of an adverse effect of pretreatment with RAAS blockers on the risk and severity of the COVID-19 infection unlikely, offering support to the recommendations of Scientific Societies and Health-Care Organizations to continue assumption of these drugs and thus avoid the well-known increase of cardiovascular risk that follows their discontinuation. The same studies showed that pretreatment with RAAS blockers did not reduce the risk and severity of the COVID19 infection, offering no support also to the counter-hypothesis, i.e. that, because ACE2 metabolizes angiotensin II from a powerful vasoconstrictor to a vasodilator or inactive substance, RAAS blocker pretreatment might protect against the SARS-CoV-2 virus. In more recent months, attention has shifted from the effects of RAAS-blocker-based pretreatment to those that may be associated with their administration during the infection, due to reports that the virusrelated death was less common in patients in whom this treatment was continued, even when compared with use of other antihypertensive agents. The reports were generated by uncontrolled studies, which limited their scientific strength and made their conclusion largely hypothetical. This is now no more the case, however, because the hypothesis has been tested by a trial (BRACE-CORONA) which has examined the outcome of hospitalized COVID-19 positive patients randomized to temporary suspension or continuation of ACE inhibitors or angiotensin receptor blocker treatment. The trial involved 34 Brazilian medical sites which recruited 659 hypertensive patients defined as having a COVID-19 infection of moderate severity and elected to take, as the primary endpoint, the number of days they were alive and out-of-hospital over a 30-day period. The design was open label and the endpoint estimate was blind. As shown in the presentation of the trial at the recent virtual meeting of the European Society of Cardiology, the number of alive and out-of-hospital patients was similar between the two groups, the mean risk ratio being 0.95 (95% confidence interval 0.90–1.01, P = 0.09) with a between-group not significant difference of just 1.1 days. The same was true for the number of patients who died (9 in either group) which exhibited a risk ratio of 0.97 and a 95% confidence interval of 0.38–2.52 (P = 0.95). This justified the conclusion that the results offered no evidence that during a COVID-19 infection ACE inhibitors and angiotensin receptor blockers affect the disease outcome, in line with the previous evidence that this is the case for pretreatment with these drugs as well. Do the results of the BRACE-CORONA trial provide a final negative answer to the hypothesis of a relationship between RAAS blockers and the SARS-CoV-2 virus? Although the BRACE-CORONA trial was correctly designed and well conducted, the trial has limitations that make confirmatory studies desirable. First, although further data may be made available in the published paper, the presentation did not include ontreatment variables, leaving without answer the possibility for the between-group outcome similarity to be driven by BP or other differences that moved to the null some direct effect of RAAS blockers on the disease severity. Second, rather than assessing the disease severity by death or need of intensive care, the trial made use of an unusual primary endpoint, i.e. patients alive and out-of-hospital, which might have been influenced by differences in dismissal criteria from hospital between medical sites. Third, although the included patients had a high prevalence of factors that are known to increase COVID-19 severity (hypertension: 100%, diabetes: >30%, obesity: >55%), mortality was so low as to prevent any meaningful analysis of an endpoint such as death as well as to use death to reliably back the primary endpoint results. Finally, the study was not planned to separately analyse the effect of ACE inhibitors and angiotensin receptor blockers, despite previous reports that during the COVID-19 infection their effect may differ Because the number of patients under ACE inhibitors was much greater than that of patients under angiotensin receptor blockers, it seems unlikely that this question will be convincingly addressed by subgroup analysis.