Epilepsy and hypertension: The possible link for sudden unexpected death in epilepsy?

Epilepsy affects about 50 million people worldwide. Sudden unexpected death in epilepsy (SUDEP) is the main cause of death in epilepsy accounting for up to 17% of all deaths in epileptic patients, and therefore remains a major public health problem. SUDEP likely arises from a combination and interaction of multiple risk factors (such as being male, drug resistance, frequent generalized tonic-clonic seizures) making risk prediction and mitigation challenging. While there is a general understanding of the physiopathology of SUDEP, mechanistic hypotheses linking risk factors with a risk of SUDEP are still lacking. Identifying cross-talk between biological systems implicated in SUDEP may facilitate the development of improved models for SUDEP risk assessment, treatment and clinical management. In this review, the aim was to explore an overlap between the pathophysiology of hypertension, cardiovascular disease and epilepsy, and discuss its implication for SUDEP. Presented herein, evidence in literature in support of a cross-talk between the renin-angiotensin system (RAS) and sympathetic nervous system, both known to be involved in the development of hypertension and cardiovascular disease, and as one of the underlying mechanisms of SUDEP. This article also provides a brief description of local RAS in brain neuroinflammation and the role of centrally acting RAS inhibitors in epileptic seizure alleviation.

Metabolomic Signature of Early Vascular Aging (EVA) in Hypertension.

Arterial stiffening is a hallmark of early vascular aging (EVA) syndrome and an independent predictor of cardiovascular morbidity and mortality. In this case-control study we sought to identify plasma metabolites associated with EVA syndrome in the setting of hypertension. An untargeted metabolomic approach was used to identify plasma metabolites in an age-, BMI-, and sex-matched groups of EVA (n = 79) and non-EVA (n = 73) individuals with hypertension. After raw data processing and filtration, 497 putative compounds were characterized, out of which 4 were identified as lysophosphaditylcholines (LPCs) [LPC (18:2), LPC (16:0), LPC (18:0), and LPC (18:1)]. A main finding of this study shows that identified LPCs were independently associated with EVA status. Although LPCs have been shown previously to be positively associated with inflammation and atherosclerosis, we observed that hypertensive individuals characterized by 4 down-regulated LPCs had 3.8 times higher risk of EVA compared to those with higher LPC levels (OR = 3.8, 95% CI 1.7-8.5, P < 0.001). Our results provide new insights into a metabolomic phenotype of vascular aging and warrants further investigation of negative association of LPCs with EVA status. This study suggests that LPCs are potential candidates to be considered for further evaluation and validation as predictors of EVA in patients with hypertension.

Untargeted Metabolomics Provides Insight into the Mechanisms Underlying Resistant Hypertension.

BACKGROUND: Resistant hypertension (RH) affects about 15-20% of treated hypertensive patients worldwide. RH increases the risk of cardiovascular events such as myocardial infarction and stroke by 50%. The pathological mechanisms underlying resistance to treatment are still poorly understood. OBJECTIVE: The main goal of this pilot study was to determine and compare plasma metabolomic profiles in resistant and non-resistant hypertensive patients. METHODS: We applied untargeted metabolomic profiling in plasma samples collected from 69 subjects with RH and 81 subjects with controlled hypertension. To confirm patients' compliance to antihypertensive treatment, levels of selected drugs and their metabolites were determined in plasma samples with the LC-ESI-TOF/MS technique. RESULTS: The results showed no statistically significant differences in the administration of antihypertensive drug in the compared groups. We identified 19 up-regulated and 13 downregulated metabolites in the RH. CONCLUSION: The metabolites altered in RH are linked to oxidative stress and inflammation, endothelium dysfunction, vasoconstriction and cell proliferation. Our results may generate new hypothesis about RH development and progression.

MASked-unconTrolled hypERtension management based on office BP or on ambulatory blood pressure measurement (MASTER) Study: a randomised controlled trial protocol.

INTRODUCTION: Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM. METHODS AND ANALYSIS: MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP <140/90 mm Hg, and at least one of the following: daytime ABP ≥135/85 mm Hg; night-time ABP ≥120/70 mm Hg; 24 hour ABP ≥130/80 mm Hg), and will be randomised to a management strategy based on OBPM (group 1) or on ABPM (group 2). Patients in group 1 will have OBP measured at 0, 3, 6, 12, 18, 24, 30, 36, 42 and 48 months and taken as a guide for treatment; ABPM will be performed at randomisation and at 12, 24, 36 and 48 months but will not be used to take treatment decisions. Patients randomised to group 2 will have ABPM performed at randomisation and all scheduled visits as a guide to antihypertensive treatment. The effects of MUCH management strategy based on ABPM or on OBPM on CV and renal intermediate outcomes (changing left ventricular mass and microalbuminuria, coprimary outcomes) at 1 year and on CV events at 4 years and on changes in BP-related variables will be assessed. ETHICS AND DISSEMINATION: MASTER study protocol has received approval by the ethical review board of Istituto Auxologico Italiano. The procedures set out in this protocol are in accordance with principles of Declaration of Helsinki and Good Clinical Practice guidelines. Results will be published in accordance with the CONSORT statement in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT02804074; Pre-results.

Prevalence and distribution of left ventricular diastolic dysfunction in treated patients with long-lasting hypertension.

BACKGROUND: Although the presence of sub-clinical left ventricular diastolic dysfunction (LVDD) increases cardiovascular risk, the current ESH/ESC guidelines do not include the presence of this condition in the list of target organ damage or cardiovascular risk charts dedicated to the hypertensive population. Several conditions may predict the LVDD occurrence, however, clustering of these factors with hypertension makes the relationship less clear. Therefore, the aim of this study was to evaluate both the occurrence and the severity of diastolic dysfunction in a large cohort of treated hypertensives. METHODS: We retrospectively analyzed records of 610 hypertensive participants of the CARE NORTH Study who consented to echocardiography and were free of overt cardiovascular disease. Mean age was 54.0 ± 13.9 years (mean ± SD), BMI 29.7 ± 4.8 kg/m2. The exclusion criteria were: established heart failure, LVEF <45%, coronary revascularization, valvular defect, atrial fibrillation, or stroke. The staging of LVDD was based on comprehensive transthoracic echocardiographic measurements. RESULTS: 49.7% percent of the patients had normal diastolic function (38.8% vs. 59.0%, females (F) vs. males (M), respectively; p < .001). Grade 1 LVDD was documented in 24.4% (27.8% and 21.6%; F and M; p = .08) and grade 2 LVDD in 19.3% (24.9% and 14.6%; F and M; p = .001) of the patients. None were diagnosed with grade 3 LVDD. In the logistic regression model, female sex, advancing age, obesity status, established diabetes mellitus, higher 24-hour SBP, and increasing LVMI were identified as the independent variables increasing the odds for the presence of LVDD, whereas blood-lowering therapy attenuated the risk. CONCLUSIONS: There is an unexpectedly high prevalence of different forms of diastolic dysfunction in treated hypertensive patients who are free of overt cardiovascular disease.

Age-dependent sympathetic neural responses to ß1 selective beta-blockade in untreated hypertension-related tachycardia.

BACKGROUND: Elevated heart rate (HR) increases cardiovascular morbidity and mortality in hypertension. The impact of beta-blockers on patient prognosis in hypertension is controversial. This study examined the age-related effects of betaxolol on HR, muscle sympathetic nerve activity (MSNA), blood pressure (BP) and sympathovagal balance in untreated males with hypertension and tachycardia. METHODS: Ten young (age 26 ± 1 years) and seven older (age 50 ± 4 years) males underwent measurement of BP, HR, HR variability (Poincare plot) and MSNA before and after 8 weeks treatment with betaxolol at the initial starting dose of 10 mg/day, which was increased to 20 mg/day once daily after 4 weeks in all subjects. RESULTS: In younger subjects, betaxolol decreased systolic BP (-13 ± 4 mm Hg, p = .01) and HR (-29 ± 4 bpm, p < .001) but not MSNA (3 ± 3 burst/min., p = 0.47) after 8 weeks. In older subjects a pronounced reduction in BP (-27 ± 7, p = .007) was accompanied by a significant decrease in MSNA (-13 ± 5 burst/min., p < .05) and HR (-17 ± 4 bpm, p = .002). SD1/SD2 ratio of Poincare plot increased in younger (0.36 ± 0.03 vs 0.51 ± 0.05, p = .004), but not in older (0.43 ± 0.08 vs 0.54 ± 0.12, p = .50) subjects. CONCLUSION: Autonomic neural responses to betaxolol are age-dependent in hypertension-related tachycardia. Betaxolol reduces sympathetic drive to the heart, but not to the peripheral vessels confirming the contribution of augmented cardiac sympathetic activity to disease pathophysiology in younger adults. In older hypertensives, the sympathovagal balance is not influenced by betaxolol. The paradoxical reduction in MSNA despite lowering of BP and HR in older patients may suggest age-related functional decrements in autonomic control and/or inhibitory effects of betaxolol on the central nervous system.

Visualizing Carotid Bodies With Doppler Ultrasound Versus CT Angiography: Preliminary Study.

OBJECTIVE: The purpose of this article is to evaluate the utility of ultrasound in identifying carotid bodies (CBs) in patients with drug-resistant arterial hypertension. SUBJECTS AND METHODS: We enrolled 13 patients with drug-resistant hypertension into a trial for surgical CB excision. CT angiography (CTA) and Doppler ultrasound (DUS) of the cervical arteries were performed before surgery. CBs were identified in a blind manner at both CTA and DUS. CBs were defined at CTA as ovoid avidly enhancing structures at the inferomedial aspect of the carotid bifurcation. At DUS, CBs were defined as ovoid solid structures in the inferomedial aspect of the bifurcation. RESULTS: CBs were identified in 12 of 13 patients (23/26 sides) using CTA and in 11 of 13 patients (18/26 sides) using DUS. Identification of CB with DUS and CTA correlated in 17 of 18 cases; in one instance, CB was identified with DUS but not CTA. There was no statistically significant difference in size and volume of CB measured by both methods. CONCLUSION: Noncarcinogenic CBs can be visualized using DUS, with good correlation of size and location compared with CTA. The findings show that DUS can be reliably used to further examine the role of CBs in cardiovascular disorders and can be used in conjunction with therapies that target CBs.

Unilateral Carotid Body Resection in Resistant Hypertension: A Safety and Feasibility Trial.

Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

Impact of obesity on cardiovascular health.

This review examines the impact of obesity on cardiovascular health. We will review first, relationship between obesity and hypertension. Second, we will describe obesity-related subclinical abnormalities in cardiovascular function and structure. Third, we will summarize evidence linking obesity to overt cardiovascular disease including coronary artery disease, congestive heart failure, stroke, arrhythmias and sudden cardiac death. Fourth, we will discuss the potential mechanisms underlying increased cardiovascular risk in obese subjects. Last, we will discuss contribution of sleep apnea to the link between obesity and cardiovascular disease. Despite recent progress in understanding epidemiologic and pathophysiological links between obesity and cardiovascular disease, several issues remain to be addressed in the future studies. There is a clear need to identify better markers of obesity-related subclinical cardiovascular damage. Furthermore, we should improve identification of obese subjects at highest cardiovascular risk.

Impact of abdominal obesity on the frequency of hypertension and cardiovascular disease in Poland - results from the IDEA study (international day for the evaluation of abdominal obesity).

INTRODUCTION: Cardiovascular disease (CVD) is a major cause of mortality, and has risk factors, which can be treated by lifestyle changes or medications. Abdominal obesity has been identified as the second strongest risk factor for myocardial infarction. OBJECTIVES: To assess the frequency of abdominal obesity and its relationship with hypertension (HT) and CVD in patients in Poland, and to compare frequencies of adiposity, HT and CVD between Poland and the North-West Europe Region, obtained in the IDEA study. METHODS: In Poland, general practitioners included 5371 patients, aged 18-80 years, eligible for analysis. Waist circumference (WC) was measured, and the presence of HT and CVD recorded. RESULTS: Increasing WC was significantly associated with HT and CVD, after adjustment for age (p<0.001). The frequency of abdominal obesity (WC >102/88 cm) was higher in Poland than in North-West Europe (36% vs 33% in men and 54% vs 45% in women, respectively, p<0.0001). Similarly, the frequency of HT in Poland was higher than in North-West Europe (47 vs 36% in men and 45 vs 30% in women, respectively p<0.001). In Poland CVD was 1.7-fold more frequent in men and 2.5-fold more frequent in women, compared with North-West Europe. CONCLUSION: In Polish adiposity, both WC and body mass index (BMI) were strongly related to HT and CVD. The frequency of abdominal obesity, obesity, HT and CVD in primary care patients is substantially higher in Poland than in North-West Europe.

Improving patient compliance with hypertension treatment: mission possible?

Hypertension, the leading cause of mortality and the third largest cause of disability, is poorly controlled worldwide. The failure to control hypertension takes an unacceptable toll on patients and their families. In addition to the personal cost, to the individual patient, uncontrolled hypertension creates huge, avoidable economic burdens when viewed in terms of the general population. Almost one-half of patients drop out entirely from treatment within 1 year. This review summarizes key challenges related to hypertension management with special focus on patient compliance. Firstly, we will present consequences of poor blood pressure control. Secondly, methods of patient compliance assessment will be reviewed. Thirdly, we will present recent studies assessing adherence with hypertension treatment. Finally, we will review potential solutions to improve patient compliance and blood pressure control which are of crucial importance for reduction of hypertension-related morbidity and mortality.

The impact of an electronic monitoring and reminder device on patient compliance with antihypertensive therapy: a randomized controlled trial.

BACKGROUND: High blood pressure (BP) significantly increases overall cardiovascular risk, the incidence of ischemic heart disease and stroke. One of the most important causes of insufficient BP control is low treatment compliance. Reminders and electronic compliance monitoring have been shown to be effective in improving patient compliance to some extent, but the combined effect has not been documented. OBJECTIVE: To assess the impact of an electronic reminder and monitoring device on patient compliance and BP control. METHODS: All patients received medical treatment with telmisartan once daily and were randomized to either electronic compliance monitoring with a reminder and monitoring device or standard therapy for 6 months. Both groups were crossed over after 6 months. Intervention effectiveness was assessed using self-reported compliance and BP. RESULTS: Data from 398 patients were analysed. In the first half of the study, patients using the device reported 91% compliance versus 85% in the control group. This difference diminished after crossover (88 versus 86%). BP was not affected. Electronic monitoring data on compliance revealed taking, dosing and timing compliance between 45 and 52% in study group 1, and between 32 and 38% in study group 2. CONCLUSION: The Helping Hand reminder device was most suitable if used for newly diagnosed hypertensive patients, when it improved compliance by 6%. With the present medical treatment, the device does not have any influence on BP control, but with less forgiving medications, the device might make a significant difference. The use of the device can be an easy and effective way to improve compliance in selected patients.

Survey of patient and physician assessment of a compliance reminder device in the treatment of hypertension.

Low compliance to therapeutic regimens can have serious impact on patient health. A variety of technologies such as tablet dispensers and reminders has been developed to improve compliance. The aim of this study was to assess the acceptance of patients and physicians with regard to the functions and usefulness of a reminder device. The respondents were participants in a trial evaluating antihypertensive medical treatment. Patients and treating physicians received a self-administered questionnaire to evaluate the device; 1194 patients and their physicians completed the questionnaire. Seventy-three per cent of patients stated that they always or mostly used the device. Overall, 78% of patients and 83% of physicians assessed the device positively. The reminder and feedback functions were assessed similarly. Sixty-four per cent of the patients stated that they would like to continue to use the device, as did 71% of the physicians. The reminder device was well accepted by a majority of patients and physicians in this study. Acceptance is an important factor for such a device to be used in everyday life and a majority of respondents wanted to continue using it. The current device could be a major help for patients on chronic medication therapy in a variety of therapies.

Antihypertensive therapy in the obese hypertensive patient.

PURPOSE OF REVIEW: Obesity is becoming recognized as one of the most important risk factors for the development of hypertension. The purpose of the review is to examine the latest evidence linking hypertension to obesity, summarize the benefits of weight reduction and present results of recent clinical trials evaluating antihypertensive treatment in obese patients. RECENT FINDINGS: Adipose tissue has been directly implicated in the pathogenesis of hypertension. Obesity has been associated with unequivocal changes in cardiovascular structure and function. In contrast to earlier studies, several recent trials included overweight and obese patients. Evidence of potential benefits of angiotensin blockade in the management of obesity hypertension is growing. Hypertension management in obese individuals is complicated by poorer response to treatment, and the increased need for multiple medications. It is important to consider obstructive sleep apnea in obese patients with resistant hypertension. SUMMARY: Several new lines of evidence suggest that drugs blocking the renin-angiotensin system might be considered as first-line therapy of obesity-related hypertension. Recent progress in understanding the mechanisms of obesity and associated disease processes might lead to development of novel therapeutic strategies. Further research in this area holds great promise for prevention of obesity-related cardiovascular disease.

Daytime, home and office blood pressures in treated hypertensive patients according to accretion of cardiovascular risk.

The relative accuracy of office, home and ambulatory blood pressure (BP) measurements has not been established in patients with metabolic syndrome (MS+). We set out to compare BP values obtained using different measurement modalities and their relationship to MS intensity in hypertensive outpatients. Office, ambulatory and home BPs and risk profile were ascertained. MS was defined according to ATPIII criteria. The study included a cohort of 104 men and 132 women with a mean age of 51.8 +/- 14.2 years; 40.3% had metabolic syndrome (MS+). The MS+ patients had higher home SBP (150 vs 142 mmHg, p < 0.01), were treated with more drugs (3.9 vs 3.0, p < 0.001) and had a poorer BP control on home measurements (11.6 vs 24.8%, p = 0.01). However, the clinical BP control rates were overall higher, and did not differ between two groups when daytime ambulatory (34.7 vs 27%) or office (26.7 vs 22.3%) values were employed. The deviation of home measurements was associated in a dose-dependent fashion with intensity of MS. Thus, in MS+ patients, the well standardized measurement protocols and equipment should be used to assess the antihypertensive efficacy. This is especially true for patients with high body mass index.