Andrea Semplicini

Cerebral small vessel disease (CSVD), which includes white matter hyperintensities, lacunes, and cerebral microbleeds, is a pathological substrate of dementia and stroke. It is correlated with high blood pressure (BP), but the detailed pathogenetic mechanisms of this correlation are unclear. This prospective population-based study correlates intracranial carotid artery calcification (ICAC), BP, and CSVD. It shows that high systolic BP and pulse pressure and low diastolic BP levels are associated with larger ICAC volume, especially in those with internal elastic lamina calcification. ICAC primary consists of intimal and internal elastic lamina calcification. Internal elastic lamina calcification is a proxy of arterial stiffness and mediates the association between BP level and CSVD through two main mechanisms: a cerebral hypoperfusion state caused by calcification and lumen narrowing of the intracranial carotid artery, and increased arterial stiffness, caused by loss of the artery to distend, increasing blood flow velocity (high systolic BP) with reduced blood flow (decreased diastolic BP). Increased pulsatile wave transmission from the aorta to the microcirculation causes direct damage to the cerebral microvasculature.

In this Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) cohort, the authors try to elucidate the relationships between cardiovascular diseases (CVD), orthostatic hypotension (OH), and the risk of developing cognitive impairment and dementia. In fact, previous studies suggest that OH is associated with an elevated risk of CVD and that, in patients with CVD, OH links to elevated dementia risk. It shows that OH is associated with a hazard ratio of 1.33 (95% CI, 1.12–1.59) for CVD. OH was not significantly associated with incident dementia in the absence of CVD occurring before dementia diagnosis (hazard ratio, 1.22 [95% CI, 0.83–1.81]). In the CVD cohort, individuals with OH had a higher dementia risk than those without OH (hazard ratio, 1.54 [95% CI, 1.06–2.23]). The clinical fallout of the study is immediate: in patients with CVD, we must try to reduce the risk of OH by appropriate pharmacological and non-pharmacological measures to reduce the risk of dementia.

Blood pressure is often elevated in hospital-admitted patients, even in the absence of known preexisting hypertension and in the absence of cardiovascular diseases. The attending physicians are, therefore, tempted to start or intensify antihypertensive treatment, which is aimed at reducing cardiovascular risk. In this cohort study using Veteran Health Administration (VHA) data of a predominately male population with multiple morbidities, one out of five older adults with elevated inpatient BP recordings received intensive antihypertensive treatment in the first 48 hours of hospitalization. Intensive treatment was associated with a greater odd of adverse events, including cardiac injury, acute kidney injury (AKI), and transfer to the Intensive Care Unit. The study is, therefore, a further confirmation that intensive antihypertensive treatment is required only if there is acute target organ damage and should not be guided only by a marked blood pressure elevation.

Salt sensitivity of blood pressure (SSBP), where BP increases or decreases >10% in response to changes in dietary salt consumption, is a heritable pathophysiological trait that accounts for 50 to 80% of essential hypertension diagnoses. A large body of evidence indicates that women are more salt-sensitive than men. The present review updates the many epidemiological, clinical, and experimental pieces of evidence that account for sex-specific mechanisms of SSBP. They include enhanced and inappropriate activation of the aldosterone-ECMR (endothelial cell mineralocorticoid receptor) axis promoting vascular dysfunction, increases in adrenal response to angiotensin II, in association with higher ECMR expression and activation of endothelial ENaC (epithelial sodium channel), that are central players in the development of endothelial dysfunction and SSBP in females.

Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. Arterial hypertension is one of the most common comorbidities of epilepsy. Arterial hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms {1}. The renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be causative. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension-related small vessel disease in adult-onset epilepsy has also been clearly demonstrated. On the contrary, the role of hypertension as an independent risk factor for post-stroke epilepsy has not been shown. However, posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. This cohort study analyzes the association between the use of specific antihypertensive therapies and the new onset of epilepsy in a large cohort of patients with hypertension in Germany. Data were available for 1,553,875 patients who had been prescribed at least one antihypertensive drug. Patients diagnosed with epilepsy before or up to three months after the index date were excluded. A total of 168,612 patients were included in propensity score matching. Patients treated with one of four antihypertensive drug classes (β-blockers, ARBs, angiotensin-converting enzyme inhibitors, and calcium channel blockers [CCBs]) were matched to each other using propensity scores. Angiotensin receptor blocker therapy was associated with a decreased incidence of epilepsy compared with other antihypertensive drug classes (except ACE inhibitors). On analysis of individual drugs within the ARB drug class, only the use of losartan was associated with a statistically significant decrease in the incidence of epilepsy. These results are in keeping with the hypothesis that the brain's renin-angiotensin-aldosterone system plays a special role in epilepsy pathology and may be associated with the hyperactivation of angiotensin II type 1 receptor and ACE signaling in astrocytes, oligodendrocytes, and microglia. Antihypertensive drugs do not represent a novel approach for preventing epilepsy in patients with arterial hypertension, but choice of antihypertensives should consider these peculiar differences.

A substantial proportion of the adult and aging population are affected by hypertension, which presents a significant risk for vascular cognitive impairment and late-life dementia. Prevention of dementia in the aging population is still an unmet target, and extensive research all over the world addresses the many pathogenetic mechanisms of hypertension-associated dementia. Previous excellent reviews from time to time already updated the results in the field for those who are only marginally involved in this topic. The present review is a further update, it summarizes in depth many new papers and provides a wide view of the fields of research in this area. Most importantly, there are new hints, poorly examined in previous revisions, such as the role of cerebral immune dysregulation, neuroinflammation, neurodegeneration, amyloid deposition, Alzheimer pathology, parallel analysis of these parameters in animal models and humans, and new ways of neuroimaging assessment. It has the merit of balancing hemodynamic, cellular, and biochemical mechanisms that are all equally relevant to understand how hypertension still represents one of the most insidious conditions that challenge brain health. Identification of each step may help to define strategies targeting the cerebral blood flow regulation, the immune system, or clearance pathways in the brain, which can be combined with already-existing antihypertensive therapy, mainly focusing upon hemodynamic effects.

Endovascular thrombectomy, with or without intravenous thrombolysis, in patients with acute ischemic stroke due to intracranial large-vessel occlusion, restores blood flow in the ischemic area of the brain, the so-called penumbral tissue. However, the risks of symptomatic intracranial hemorrhage and other forms of reperfusion injury remain high. Elevated blood pressure is a modifiable factor to prevent reperfusion injury, but clinical guidelines have continued to recommend a conservative level of blood pressure control (systolic pressure of <180mmHg and diastolic pressure of 105mmHg) before and after endovascular thrombectomy, as recommended for patients eligible for intravenous thrombolysis after acute ischemic stroke. ENCHANTED2/MT is the largest randomized controlled trial of intensive blood pressure lowering after endovascular therapy for acute ischemic stroke from intracranial large-vessel occlusion to date. After endovascular treatment, 821 patients were randomly assigned to more intensive treatment (systolic blood pressure target <120mmHg) or less intensive treatment (target 140-180mmHg) to be achieved within 1h and sustained for 72h. The primary result was that more intensive blood pressure lowering to a systolic target of less than 120mmHg was associated with worse functional outcomes (measured on the modified Rankin scale) at 90 days when compared with a less intensive systolic target of 140-180mmHg, and this adverse effect manifested as neurological deterioration within 7 days of commencing treatment. These results indicate that a more intensive blood pressure management strategy to achieve a systolic blood pressure target of less than 120mmHg after successful endovascular thrombectomy should be avoided in clinical practice. They also highlight the complex relationships between perfusion pressure and organ protection in the acute setting, at variance with long term effect of antihypertensive treatment on cardiovascular risk.

The Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive blood pressure control reduced cardiovascular morbidity and mortality {1}. However, the longer-term effect of intensive treatment on cardiovascular and all-cause mortality after the end of trial (i.e. the legacy effect) has not been evaluated. The current study aims to evaluate the longer-term legacy effect of intensive treatment in SPRINT on mortality with passive follow-up using administrative data sources. The patients were randomized to systolic blood pressure (SBP) goal of less than 120mmHg (intensive treatment group; n=4678) vs less than 140mmHg (standard treatment group; n=4683), between 2010 and 2015. Extended observational follow-up for mortality was completed via the US National Death Index from 2016 through 2020. In a subset of 2944 trial participants, outpatient SBP from electronic health records during and after the trial were also examined. The study shows that over a median (IQR) intervention period of 3.3 (2.9-3.9) years, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49-0.89) and all-cause mortality (HR, 0.83; 95% CI, 0.68-1.01). However, at the median (IQR) total follow-up of 8.8 (8.3-9.3) years, there was no longer evidence of benefit for cardiovascular mortality (HR, 1.02; 95% CI, 0.84-1.24) or all-cause mortality (HR, 1.08; 95% CI, 0.94-1.23). The estimated mean outpatient SBP among participants randomized to intensive treatment increased from 132.8mmHg (95% CI, 132.0-133.7) at 5 years to 140.4mmHg (95% CI, 137.8-143.0) at 10 years following randomization. These results show that the mortality benefits associated with intensive treatment quickly disappear after the trial intervention was discontinued, most likely because the difference in SBP between treatment groups diminished steadily over time, with no detectable difference in SBP approximately 9 years after randomization. They indicate that the beneficial effect of intensive treatment among adults with hypertension appears to diminish quickly if intensive BP control is not sustained. Furthermore, they confirm that the benefits of antihypertensive treatment last as long as blood pressure is kept low and stress the importance of continuous treatment and compliance

Adequate hypertension control reduces the risk of major cardiovascular events, including stroke, ischemic heart disease, and cardiovascular death. Normal blood pressure, at 24h ambulatory monitoring, exhibits a diurnal rhythm, with lower pressures during night ­time sleep, followed by a morning increase or surge in blood pressure. The risk of adverse cardiovascular outcomes is increased in people whose blood pressure does not have the typical diurnal variation. Furthermore, cardiovascular events are temporally associated with the morning blood pressure surge. This study investigates if evening dosing of antihypertensive is more effective at preventing the long-­term cardiovascular sequelae of hypertension than morning dosing. This Treatment in Morning versus Evening (TIME) study is a large, pragmatic, decentralised, prospective, randomised, open-label, blinded-endpoint, superiority trial conducted in the UK, comparing cardiovascular outcomes in adults with hypertension randomly assigned to evening versus morning dosing of their usual antihypertensive medications. To this aim, 21,104 hypertensives were randomly assigned to evening (n=10,503) or morning (n=10,601) dosing groups. After a median follow-up of 5.2 years, a primary endpoint event occurred in 362 (3.4%) participants assigned to evening treatment (0.69 events [95% CI 0.62-0.76] per 100 patient-years) and 390 (3.7%) assigned to morning treatment (0.72 events [95% CI 0.65-0.79] per 100 patient-years; unadjusted hazard ratio 0.95 [95% CI 0.83-1.10]; p=0.53). No safety concerns were identified. The conclusions of the authors are that clinicians should focus on selecting appropriate medications and supporting adherence to agreed treatment plans, instead of on time of dosing. They have been included in the 2022 International Society of Hypertension (ISH) Position Paper on “Bedtime dosing of antihypertensive medications” {1}. The ISH Key Recommendations are the following: • A key aim of blood pressure-lowering treatment should be to achieve complete 24h control of BP by using long-acting antihypertensive medications. • Bedtime drug dosing should not be routinely recommended in clinical practice. • Treatment of hypertension should be based on long-acting agents in monotherapy or in combinations administered in a single morning dose, as applied in the vast majority of long-term outcome hypertension trials. Trial registry details: ISRCTN18157641.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are synthetic chemicals, widely used in industrial applications and consumer products. They are nowadays ubiquitous and have been estimated to contaminate drinking water of million people. They are of public health concern because they are persistent in the environment and in the human body. Due to structural similarity to fatty acids, PFAS may interfere with the action of PPARs (peroxisome proliferator-activated receptors), and their signaling pathways, and thus, modulate metabolic pathways. PFAS exposure causes oxidative stress and endothelial dysfunction, thereby affecting the cardiovascular system. This study evaluates the effects of perfluoroalkyl and polyfluoroalkyl substances on incident hypertension among midlife women, using a prospective cohort of 1,058 women initially free of hypertension, with annual follow-up visits from 1999 to 2017. It shows that higher perfluorooctane sulfonate, perfluorooctanoate, and 2-(N-ethyl-perfluorooctane sulfonamido) acetate are associated with 42%, 47%, and 42% higher risks of hypertension, respectively, comparing the highest to the lowest tertile. Participants with higher overall perfluoroalkyl and polyfluoroalkyl substances concentrations are associated with a 71% increase in the risk of hypertension. Therefore, perfluoroalkyl and polyfluoroalkyl substances are potentially modifiable risk factors for hypertension and cardiovascular diseases. Recognition of this new environmental cardiovascular risk factor is of paramount importance for developing effective strategies to reduce PFAS exposure to prevent the development of hypertension and to reduce the global burden of cardiovascular diseases.