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Hypertension does not recognize obvious pathogenic causes in the majority of patients (essential hypertension). However, a secondary underlying cause of hypertension can be recognized in 5-10% of unselected hypertensive patients, and this prevalence may increase to more than 20% in patients with hypertension that is difficult to control or frankly resistant to treatment. In children, secondary hypertension is most often due to aortic coarctation, distal thoracic or abdominal aortic stenosis, or specific gene mutations. In adults or elderly individuals, secondary hypertension is most often due to atherosclerotic renal artery stenosis, primary hyperaldosteronism, and Cushing's disease or syndrome. Parenchymal nephropathy and hyperparathyroidism can cause hypertension at all ages, while pheochromocytoma and paraganglioma tend to occur more often in adolescents or young adults. In general, secondary hypertension should be suspected in subjects with: (a) onset of hypertension under 30 years of age especially if in the absence of hypertensive family history or other risk factors for hypertension; (b) treatment-resistant hypertension; c) severe hypertension (>180/110 mmHg), malignancy, or hypertensive emergencies; d) rapid rise in blood pressure values in previously well controlled patients. Any clinical signs suspicious or suggestive of hypertension from endocrine causes, a "reverse dipping" or "non-dipping'" profile at 24 h ambulatory blood pressure monitoring not justified by other factors, signs of obvious organ damage may be helpful clues for diagnosis. Finally, patients snoring or with clear sleep apnea should also be considered for possible secondary hypertension.

Superiority trials are designed to test the hypothesis that a given diagnostic or therapeutic strategy is better than (i.e. "superior to") placebo or an active control. Conversely, non-inferiority trials test the hypothesis that a newer (i.e. alternative) strategy is not "unacceptably worse" than a control (i.e. "traditional", or "older") strategy. Non-inferiority trials are increasingly conducted in clinical medicine more often when a "newer" strategy is supposed to offer a relevant advantage in terms other than clinical efficacy (i.e. better tolerability, less cost, simpler regimen, etc.) versus a "gold standard" traditional strategy. The principle underlying non-inferiority trials is that the above advantage justifies the preferential use of the newer strategy in the clinical practice even if the clinical efficacy of the "new" appears to be a bit worse than that of the "old", albeit not unacceptably worse (i.e. not beyond a pre-specified value). The demonstration of non-inferiority requires that the confidence interval of the point estimate (e.g. the hazard ratio) does not cross a pre-specified limit. The definition of such pre-specified limit, the so called "non-inferiority margin", is a pivotal point when planning non-inferiority trials. It denotes the maximally tolerated worse effect of the alternative strategy, compared with the traditional one, required to conclude that an alternative strategy is non-inferior to the traditional "gold standard". The non-inferiority margin is derived from previous trials evaluating the efficacy of the traditional strategy vs placebo. We reviewed the principles and the practical aspects in the design and conduct of non-inferiority trials.

Blood pressure progressively increases with age and hypertension represents one of the most prevalent and potentially modifiable risk factors in older adults. Because of the high prevalence of multiple comorbidities and frailty, the management of hypertension in the elderly is more challenging than in younger patients. It is now soundly established from randomized clinical trials the benefit from treating hypertension in older hypertensive patients, including those over the age of 80 years. Although the prognostic benefit of active treatment is indisputable, it is still debated the ideal blood pressure target in the geriatric population. A critical review of trials analyzing the benefits of different blood pressure targets in elderly patients supports the notion that targeting a more intensive blood pressure goal may provide benefits which considerably outweigh the risks of unwanted effects (including hypotension, falls, acute kidney injury, and electrolyte disturbances). Furthermore, these prognostic benefits persist even in older patients who are frail. However, the optimal blood pressure control should achieve the maximum preventive benefits without causing harms or complications.In conclusion, age itself is not a barrier for treatment and it should not preclude a more intensive treatment of hypertension. Treatment should be personalized to achieve a more strict control of blood pressure (to prevent serious cardiovascular events), and to avoid over-treating frail older adults.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread across the world, killing more than 4 million individuals globally, with 240 million individuals being confirmed by laboratory tests. Among different therapeutic strategies to prevent SARS-CoV-2 infection, vaccines are the most promising approach for curbing the pandemic. They elicit an immune neutralizing response and thus offer protection against coronavirus disease 2019 (COVID-19). However, some questions regarding the safety of COVID-19 vaccines have been raised and based on sparse reports of severe systemic reactions after vaccination. Among these, evidences on the potential effect of vaccination on the acute rise in blood pressure have been recently accrued. Approved vaccines in Europe increase the endogenous synthesis of SARS-CoV-2 Spike proteins from a variety of cells. Once synthetized in the cells reached by the vaccine, the Spike proteins first assemble in the cytoplasm and then migrate to the cell surface to protrude with a native-like conformation. Spike proteins are recognized by the immune system which rapidly develops an immune response. Furthermore, the Spike proteins assembled in the cells which are eventually destroyed by the immune response circulate in the blood as free-floating forms. Free-floating Spike proteins may interact with angiotensin-converting enzyme 2 (ACE2) receptors leading to internalization, degradation, and dysregulation of the catalytic activities of these receptors. The consequent loss of ACE2 receptor activity leads to a rapid drop in the generation of angiotensin1,7 resulting from inactivation of angiotensin II. The imbalance between angiotensin II (overactivity) and of angiotensin1,7 (deficiency) might play a role in the genesis of acute elevation in blood pressure.

Some Authors recently suggested that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be discontinued, even temporarily, given the current pandemic of SARS-CoV-2 virus. The suggestion is based on the hypothesis that ACE-inhibitors and ARBs may favor the entry and diffusion of SARS-CoV-2 virus into the human cells. ACE-inhibitors and ARBs may increase the expression of ACE2 receptors, which are the sites of viral entry into the human organism. ACE2 receptors are ubiquitous, although they are extremely abundant on the cell surface of type 2 pneumocytes. Type 2 pneumocytes are small cylindrical alveolar cells located in close vicinity to pulmonary capillaries and responsible for the synthesis of alveolar surfactant, which is known to facilitate gas exchanges. The increased expression of ACE2 for effect of ACE-inhibitors and ARBs can be detected by increased production of angiotensin1-7 and mRNA related to ACE2. There is the fear that the increased expression of ACE2 induced by ACE-inhibitors and ARBs may ultimately facilitate the entry and diffusion of the SARS-CoV-2 virus. However, there is no clinical evidence to support this hypothesis. Furthermore, available data are conflicting and some counter-intuitive findings suggest that ARBs may be beneficial, not harmful. Indeed, studies conducted in different laboratories demonstrated that ACE2 receptors show a down-regulation (i.e. the opposite of what would happen with ACE-inhibitors and ARBs) for effect of their interaction with the virus. In animal studies, down-regulation of ACE2 has been found as prevalent in the pulmonary areas infected by virus, but not in the surrounding areas. In these studies, virus-induced ACE2 down-regulation would lead to a reduced formation of angiotensin1-7 (because ACE2 degrades angiotensin II into angiotensin1-7) with consequent accumulation of angiotensin II. The excess angiotensin II would favor pulmonary edema and inflammation, a phenomenon directly associated with angiotensin II levels, along with worsening in pulmonary function. Such detrimental effects have been blocked by ARBs in experimental models. In the light of the above considerations, it is reasonable to conclude that the suggestion to discontinue ACE-inhibitors or ARBs in all patients with the aim of preventing or limiting the diffusion of SARS-CoV-2 virus is not based on clinical evidence. Conversely, experimental studies suggest that ARBs might be useful in these patients to limit pulmonary damage through the inhibition of type 1 angiotensin II receptors. Controlled clinical studies in this area are eagerly awaited. This review discusses facts and theories on the potential impact of ACE-inhibitors and ARBs in the setting of the SARS-CoV-2 pandemic.

The SPRINT study tested the hypothesis that hypertensive patients randomized to a more intensive treatment, aimed at lowering systolic blood pressure (BP) below 120 mmHg have a lower incidence of major cardiovascular events when compared to patients randomized to a less intensive treatment (systolic BP reduction below 140 mmHg). Overall, 9361 patients were randomized to the more intensive (n=4678) or less intensive (n=4683) antihypertensive treatment. The study was prematurely interrupted because of an excess benefit in the more intensive arm. Indeed, the group randomized to the more intensive arm showed, when compared to the group randomized to the less intensive arm, a 25% reduction in the primary endpoint (1.65 vs 2.19% per year; p<0.001), a 43% reduction in cardiovascular death (0.25 vs 0.43%; p=0.005), a 27% reduction in all-cause death (1.03% vs 1.40%; p=0.003) and a 38% reduction in hospitalizations for heart failure (0.41 vs 0.67%; p<0.002). Unexpectedly, there was no significant reduction in the risk of stroke (not significant 11% reduction). The SPRINT study unequivocally shows that, in hypertensive patients with systolic BP ≥130 mmHg and no history of diabetes, previous stroke and polycystic renal disease, we should try to lower systolic BP to levels below 120 mmHg with the objective to lower the incidence of heart failure in addition to all-cause and cardiovascular death. Future guidelines on the management of patients with hypertension should implement the results of the SPRINT study.

Unlabelled: The Italian Registry of Dialysis and Transplantation (RIDT) has recently resumed the collection of data of patients on RRT in Italy. Data were requested to Regional Registries for the years 2011-2013 and they contributed according to their possibilities. Eighteen Regions or autonomous Provinces provided data with various degrees of completeness and this made possible to bridge the gap between the current and the previous census (referring to 2010)., Results: Incidencedata were associated to a sample with a coverage of 77% of the national population (46/60 million inhabitants). Patients who started dialysis in these three years were, respectively, 168, 166 and 160 patients pmp. If we project this data to the national population is reasonable to think that 9500-10000 patients per year start the dialytic treatment., Prevalence: The prevalence of patients on dialysis in Italy range, in the 10 years of RIDT, between 750 and 825 patients pmp. Based on this we can reasonably estimate that in Italy there are 45-49000 dialysis patients. Incidence and prevalence vary widely in different regions. Mortalityon dialysis in Italy during the period 2011-2013 was on average 16.2 per 100 patient-years (95% CI: 16.1-16.7) with regional variation smaller than that observed in incidence and prevalence., Conclusions: In this paper, data analysis are presented in a direct and non comparative manner. However, it provides information on the status of the RRT in Italy and the temporal consistency of the data is a proof of their validity. Registry data were published in the official site of Italian Registry that can be reached through the website of SIN (www.sin-italy.org).

Recently, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorization for liraglutide for the treatment of type 2 diabetes mellitus. Liraglutide is the first human glucagon-like peptide-1 (GLP-1) analog, based on the structure of native GLP-1, with pharmacokinetic properties suitable for once-daily dosing. In the phase III Liraglutide Effect and Action in Diabetes (LEAD) program, liraglutide has been shown to lower glycated hemoglobin to the same extent or more than other antidiabetic drugs including insulin. Liraglutide determines favorable changes in the global cardiovascular risk profile because its use is associated with weight loss, blood pressure reduction, as well as improvements of several cardiovascular risk biomarkers. Liraglutide is generally well tolerated, the most frequently reported adverse effect is transient nausea, and it does not seems to have significant interactions with medications commonly used for cardiovascular prevention. This article reviews, for the practicing cardiologist, the results of the LEAD program and explores liraglutide potentials for cardiovascular prevention in type 2 diabetes mellitus.

Traditionally, diagnosis and management of arterial hypertension are based on blood pressure (BP) measurements taken in the physician's office. However, 24-h noninvasive ambulatory BP monitoring is increasingly used in patients with essential hypertension. Several prospective studies provided unequivocal evidence of an independent association between ambulatory BP and risk of cardiovascular disease in the general population and hypertensive patients. Ambulatory BP is a better predictor of cardiovascular morbidity and mortality than office BP after adjustment for traditional cardiovascular risk factors such as age, sex, smoking status, baseline office BP, and use of antihypertensive drugs. The more accurate prognostic value of ambulatory BP may be related to the closer association with hypertension-related organ damage such as left ventricular mass, intima-media thickness, and microalbuminuria. The superiority of ambulatory over clinic BP in predicting clinical outcome and the most appropriate way of interpreting results of ambulatory BP monitoring will be discussed in this review.

In a given hypertensive patient, clinically overt cardiovascular disease is often preceded by a number of signs of target organ damage at the cardiac, arterial and renal levels. These changes have been collectively defined "pre-clinical cardiovascular disease", and carry a substantially increased risk for future cardiovascular complications. The present article examines the relationship between blood pressure components and target organ damage in essential hypertension. Arterial pressure can be split into a steady component (represented by the mean arterial pressure), which is a measure of the average level of pressure in a given artery, and a pulsatile component (represented by the pulse pressure), which estimates the cyclic oscillations around the mean. All blood pressure components show a positive, linear correlation with left ventricular mass, both in the general population and in patients with essential hypertension. However, the association is significantly stronger for the steady blood pressure components (systolic and mean arterial pressure) than for the pulse pressure. Available data regarding arterial changes suggest that the association is partly different. The majority of available studies show that large-artery intima-media thickening and discrete atherosclerotic plaques are better predicted by pulse pressure than by other blood pressure components, particularly in the elderly. After the age of 60, there is clear-cut evidence for a J-shaped relationship between diastolic blood pressure and arterial thickening or plaques, while for younger age groups the relationship appears to be linear. These data might offer an explanation for the observed superior prognostic value of pulse pressure in the elderly. The relationship between the different blood pressure components and renal damage is more controversial. In summary, pulsatile, cyclic stress (as represented by pulse pressure) appears to be more important in determining arterial changes in hypertensive patients, while steady blood pressure components play a dominant role in the development of hypertensive left ventricular hypertrophy.

A disease of the legs, and more specifically of the feet, is a frequent occurrence in diabetic patients and can lead to the major risk of amputation. The pathogenesis of this disease is complex and due to vascular damage and neuropathy. The neuropathic ulcer is a typical clinical manifestation of the "diabetic foot". The pathogenesis of this manifestation is discussed. The most important thing is to prevent this disease. The diabetologist must regularly examine the feet of the patients and measure the foot pressure. We discuss a new instrument, the Dynamic System, which we believe of great help to diabetologist in measuring the foot pressure of diabetic patients.