Hypotensive episodes at 24-h ambulatory blood pressure monitoring predict adverse outcomes in Parkinson's disease.

PURPOSE: Neurogenic orthostatic hypotension (nOH) is a frequent nonmotor feature of Parkinson's disease (PD), associated with adverse outcomes. Recently, 24-h ambulatory blood pressure monitoring (ABPM) showed good accuracy in diagnosing nOH. This study aims at evaluating the prognostic role of ABPM-hypotensive episodes in predicting PD disability milestones and mortality and comparing it to the well-defined prognostic role of bedside nOH. METHODS: Patients with PD who underwent ABPM from January 2012 to December 2014 were retrospectively enrolled and assessed for the development of falls, fractures, dementia, bed/wheelchair confinement, hospitalization, and mortality, during an up-to-10-year follow-up. Significant ABPM-hypotensive episodes were identified when greater than or equal to two episodes of systolic BP drop ≥ 15 mmHg (compared with the average 24 h) were recorded during the awakening-to-lunch period. RESULTS: A total of 99 patients (74% male, age 64.0 ± 10.1 years, and PD duration 6.4 ± 4.0 years) were enrolled. At baseline, 38.4% of patients had ABPM-hypotensive episodes and 46.5% had bedside nOH. On Kaplan-Meier analysis, patients with ABPM-hypotensive episodes showed earlier onset of falls (p = 0.001), fractures (p = 0.004), hospitalizations (p = 0.009), bed/wheelchair confinement (p = 0.032), dementia (p = 0.001), and shorter survival (8.0 versus 9.5 years; p = 0.009). At Cox regression analysis (adjusted for age, disease duration, Charlson Comorbidity Index, and Hoehn and Yahr stage) a significant association was confirmed between ABPM-hypotensive episodes and falls [odds ratio (OR) 3.626; p = 0.001), hospitalizations (OR 2.016; p = 0.038), and dementia (OR 2.926; p = 0.008), while bedside nOH was only associated with falls (OR 2.022; p = 0.039) and dementia (OR 1.908; p = 0.048). CONCLUSIONS: The presence of at least two ABPM-hypotensive episodes independently predicted the development of falls, dementia, and hospitalization, showing a stronger prognostic value than the simple bedside assessment.

Quality of life in primary aldosteronism: A prospective observational study.

BACKGROUND: Previous studies suggested that patients affected by primary aldosteronism (PA) have impaired quality of life (QOL) compared to the general population, but a direct comparison with patients affected by essential hypertension (EH) has never been performed. The aim of the study was to compare the QOL of patients affected by PA to the QOL of patients affected by EH. MATERIAL AND METHODS: We designed a prospective observational study comparing the QOL of patients with PA and carefully matched patients with EH before and after treatment. We recruited 70 patients with PA and 70 patients with EH, matched for age, sex, blood pressure levels and intensity of antihypertensive treatment. We assessed QOL at baseline and after specific treatment for PA or after optimization of medical therapy for patients with EH. RESULTS: Patients with PA displayed impaired QOL compared with the general healthy population, but similar to patients with EH. Both laparoscopic adrenalectomy and treatment with mineralocorticoid receptor antagonist allowed an improvement of QOL in patients with PA, that was more pronounced after surgical treatment. Optimization of blood pressure control by implementation of antihypertensive treatment (without MR antagonists) allowed a minimal improvement in only one of eight domains in patients with EH. CONCLUSIONS: Patients with PA have impaired QOL, which is likely caused by uncontrolled hypertension and the effects of intensive antihypertensive treatment. Surgical and medical treatment of PA allows a significant improvement of QOL, by amelioration of blood pressure control and, after surgical treatment, by reduction of antihypertensive treatment.

Knowledge on arterial hypertension in general population: Results from a community pharmacy screening program.

BACKGROUNDS AND AIMS: Hypertension is a risk factor for renal, cardiovascular and cerebrovascular diseases. It is responsible for a large proportion of overall morbidity and mortality every year. Hypertension-mediated organ damage is largely not reversible. For these reasons, prevention has primary importance: sensibilization of population on hypertension-related consequences is essential for therapeutic adherence and reduction of unhealthy lifestyle behaviour. This study aimed to evaluate awareness about hypertension among community pharmacies customers. METHODS AND RESULTS: A questionnaire about hypertension was collected by 2731 customers from 94 community pharmacies in North West Italy, during a hypertension screening program. Hypertension awareness was unsatisfactory in a large proportion of the sample, with only 15% of subjects having an overall good level of knowledge. Furthermore, lower awareness was associated to higher blood pressure values (132/79 ± 19/11 mmHg vs 128/78 ± 18/10 mmHg, p < 0.001) and subjects resulted hypertensive or uncontrolled despite antihypertensive therapy, presented worse questionnaire scores (4.7 ± 1.9 vs 4.9 ± 2.0, p = 0.03). CONCLUSION: Knowledge about hypertension is largely unsatisfactory among population. Community pharmacies may play as a setting for health education and hypertension screening.

Primary Aldosteronism and Obstructive Sleep Apnea: Casual Association or Pathophysiological Link?

The coexistence of aldosterone oversecretion and obstructive sleep apnea is frequently observed, especially in patients with resistant hypertension, obesity, and metabolic syndrome. Since aldosterone excess and sleep apnea are both independently associated with an increased risk of cardiovascular disease, to investigate whether their coexistence might be attributed to common predisposing conditions, such as metabolic disorders, or to an actual pathophysiological interconnection appears of great importance. Fluid overload and metabolic abnormalities relating to aldosterone oversecretion may be implicated in obstructive sleep apnea development. Nocturnal intermittent hypoxia may in turn exacerbate renin-angiotensin-aldosterone system activity, thus leading to hyperaldosteronism. Furthermore, fat tissue excess and adipocyte secretory products might predispose to both sleep apnea and aldosterone oversecretion in subjects with obesity. Consistent with these evidences, obstructive sleep apnea frequently affects patients with primary aldosteronism. Conversely, whether primary aldosteronism is more prevalent in individuals affected by obstructive sleep apnea compared to the general population remains controversial.

Pulse wave velocity and short-term outcome in patients requiring intravascular volume expansion: a pilot study.

BACKGROUND: Fluid therapy has a pivotal role in the management of acutely ill patients. However, whether or not a patient can tolerate additional intravascular volume is controversial and optimal strategy is unknown. Carotid femoral pulse wave velocity (cfPWV) evaluates arterial stiffness. OBJECTIVE: To determine whether cfPWV can predict the ability of patients to tolerate clinically indicated acute fluid expansion. METHODS: 50 consecutive patients requiring intravascular volume expansion were prospectively recruited in intensive care units. All subjects underwent transthoracic echocardiography, pulmonary ultrasound assessment, and a cfPWV study (S. Giovanni Bosco Hospital in Turin, Italy, between 2015 and 2016) at baseline and after 24 hours. Acute outcomes were registered at 24 hours ("soft" end points) and 30 days ('hard' end points: death, acute myocardial infarction, stroke, occurrence of atrial fibrillation, need for dialysis) after initial fluid therapy. Multivariate logistic regression was used to assess association of the initial cfPWV with outcomes. RESULTS: cfPWV was significantly higher (10.6±3.6 vs 7.4±2.2 m/s, P<0.0001) in subjects who met the prespecified combined endpoints (hard or soft) than in those who did not. After adjustment for confounding factors, initial cfPWV was significantly and independently associated with the occurrence of hard events (OR=2.8 (95% CI 1.36 to 5.97), P=0.005; area under the receiver operating characteristic curve 84%). cfPWV of <9 m/s had a negative predictive value of 93%, excluding hard events associated with fluid expansion. CONCLUSION: cfPWV appears to reflect the ability of the patient to tolerate an intravascular fluid expansion when clinically indicated. Increased cfPWV could help to identify subjects at greater risk of developing signs and symptoms of fluid overload.

Assessment of a non-physician screening program for hypertension and cardiovascular risk in community pharmacies.

BACKGROUND AND AIMS: The strategic role of prevention in hypertension setting is well known but, with the only exception of annually events promoted by international scientific societies, no other screening campaigns are available. Aim of this study was to assess the feasibility of a non-physician pharmacy-based screening program and to describe the cardiovascular risk and the BP status of participating subjects. METHODS AND RESULTS: 2731 costumers participated to the screening program, answering to a questionnaire about personal cardiovascular risk and measuring their BP with an Omron HEM 1040-E. Since no threshold for hypertension diagnosis is currently available for community pharmacies BP measurements, we assessed high BP prevalence according to 3 different cut-offs (≥140/90, ≥135/85 and ≥ 130/80 mmHg) and compared normotensives and hypertensives on major cardiovascular risk factors. According to the proposed cut-offs, prevalence of hypertension was respectively of 31%, 45% and 59.5%, and it increased among younger subjects (31-65 y) when the lowest cut-offs were applied. High BP was found in a large percentage of subjects self-declared on-/not on-treatment (uncontrolled hypertensives) or normotensives (presumptive hypertensives) and among those not aware of their own BP values (presumptive hypertensives). Prevalence of CV risk factors was higher in hypertensives than in normotensives. CONCLUSIONS: Our findings demonstrated that a community pharmacy-based screening is feasible and attracts the interests of many subjects, improving awareness on their BP status. The screening was also showed to be useful in order to detect potentially uncontrolled and/or suspected new hypertensives, especially among young adults, to refer to general practitioners for confirmatory diagnosis or further evaluation.

Nation-wide hypertension screening in Italy: data from May Measurements Month 2017-Europe.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative organized by the International Society of Hypertension aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programs worldwide. A similar approach has been used in Italy since 2012, showing inadequate awareness of the consequences of hypertension, a generally increased cardiovascular risk and unsatisfactory BP control in 36% of interviewed individuals. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017, during the joint MMM and World Hypertension Day events. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. Screenings were conducted both in cities and villages, indoor and outdoor, by health personnel. Eighty-five sites, involving approximately 300 investigators, took part in MMM17/World Hypertension Day in Italy, screening 10 076 individuals during a month-long period. After multiple imputation, 3099 participants were found (30.8%) to have high BP levels. This was the biggest opportunistic BP screening in a single time-point ever reported in Italy. A significant proportion of individuals had high BP, although it was not possible to differentiate between known treated hypertensive patients with inadequate BP control and as yet undiagnosed hypertensive individuals. Opportunistic screening can reach a significant number of individuals, being a powerful tool for raising awareness and carrying out BP screening.

Diagnostic approach to low-renin hypertension.

Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the "classical" RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low-renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low-renin levels are expression of a physiological response to sodium-volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low-renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low-renin hypertension, enlightening the novelties in genetics of the familial forms.

Therapeutic drug monitoring-guided definition of adherence profiles in resistant hypertension and identification of predictors of poor adherence.

AIMS: Arterial hypertension is an important cardiovascular risk factor. A substantial proportion of patients show resistance to antihypertensive treatment but poor adherence to medication regimens is also a significant cause of treatment failure. In this context, therapeutic drug monitoring (TDM) could be useful. The objective of this study was to assess adherence to treatment in patients with resistant hypertension by TDM and to identify parameters that predict nonadherence. METHODS: Liquid chromatography tandem mass spectrometry was used to quantify a wide panel of antihypertensive drugs in human plasma to assess treatment compliance. Associations between TDM-determined adherence profiles, self-reported adherence and other patient-related clinical, anthropometric or demographic features were evaluated as potentially useful pre-TDM predictors of poor adherence. RESULTS: TDM was performed on 50 patients with suspected resistant hypertension: 24% of patients partially complied to treatment and 18% were nonadherent. No concordance was observed with questionnaire results, while nonadherence was associated with high diastolic blood pressure, high heart rate, previous onset of stroke and previous use of invasive treatments, including renal denervation or baroreceptor stimulation. CONCLUSIONS: This evidence highlights the high prevalence of poor adherence in patients with resistant hypertension and the need for caution in using invasive approaches. These preliminary data require validation in a larger cohort, to confirm the need for TDM in routine clinical practice.

Role of Cryptochrome-1 and Cryptochrome-2 in Aldosterone-Producing Adenomas and Adrenocortical Cells.

Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3ß-hydroxyl-steroid dehydrogenase (Hsd3b6), the murine counterpart to the human type I 3ß-hydroxyl-steroid dehydrogenase (HSD3B1) gene. In the present study, we evaluated the role of CRY1 and CRY2 genes, and their potential interplay with HSD3B isoforms in adrenal pathophysiology in man. Forty-six sporadic aldosterone-producing adenomas (APAs) and 20 paired adrenal samples were included, with the human adrenocortical cells HAC15 used as the in vitro model. In our cohort of sporadic APAs, CRY1 expression was 1.7-fold [0.75⁻2.26] higher (p = 0.016), while CRY2 showed a 20% lower expression [0.80, 0.52⁻1.08] (p = 0.04) in APAs when compared with the corresponding adjacent adrenal cortex. Type II 3ß-hydroxyl-steroid dehydrogenase (HSD3B2) was 317-fold [200⁻573] more expressed than HSD3B1, and is the main HSD3B isoform in APAs. Both dehydrogenases were more expressed in APAs when compared with the adjacent cortex (5.7-fold and 3.5-fold, respectively, p < 0.001 and p = 0.001) and HSD3B1 was significantly more expressed in APAs composed mainly of zona glomerulosa-like cells. Treatment with angiotensin II (AngII) resulted in a significant upregulation of CRY1 (1.7 ± 0.25-fold, p < 0.001) at 6 h, and downregulation of CRY2 at 12 h (0.6 ± 0.1-fold, p < 0.001), through activation of the AngII type 1 receptor. Independent silencing of CRY1 and CRY2 genes in HAC15 cells resulted in a mild upregulation of HSD3B2 without affecting HSD3B1 expression. In conclusion, our results support the hypothesis that CRY1 and CRY2, being AngII-regulated genes, and showing a differential expression in APAs when compared with the adjacent adrenal cortex, might be involved in adrenal cell function, and in the regulation of aldosterone production.

Liddle Syndrome: Review of the Literature and Description of a New Case.

Liddle syndrome is an inherited form of low-renin hypertension, transmitted with an autosomal dominant pattern. The molecular basis of Liddle syndrome resides in germline mutations of the SCNN1A, SCNN1B and SCNN1G genes, encoding the α, ß, and γ-subunits of the epithelial Na⁺ channel (ENaC), respectively. To date, 31 different causative mutations have been reported in 72 families from four continents. The majority of the substitutions cause an increased expression of the channel at the distal nephron apical membrane, with subsequent enhanced renal sodium reabsorption. The most common clinical presentation of the disease is early onset hypertension, hypokalemia, metabolic alkalosis, suppressed plasma renin activity and low plasma aldosterone. Consequently, treatment of Liddle syndrome is based on the administration of ENaC blockers, amiloride and triamterene. Herein, we discuss the genetic basis, clinical presentation, diagnosis and treatment of Liddle syndrome. Finally, we report a new case in an Italian family, caused by a SCNN1B p.Pro618Leu substitution.

Is Primary Aldosteronism Still Largely Unrecognized?

Primary aldosteronism (PA) was first reported by Jerome W. Conn in 1954 when it was considered a rare disorder, only suspected in cases of hypertension and spontaneous hypokalemia. Over the last 30 years, with the wide application of the plasma aldosterone to plasma renin activity ratio as screening test, the clinical spectrum of PA has dramatically changed. Different studies displayed significant differences in term of patients investigated, diagnostic criteria and hormonal assays; however, large prospective studies with robust diagnostic criteria indicated that the prevalence of PA is around 6% of the general hypertensive population and 11% of the patients referred to hypertension centers. In light of these epidemiological studies, the Endocrine Society Guideline recommends the screening for PA of around 50% of patients with hypertension, and identifies the categories of patients at high risk for the disease. However, clinical data obtained from "real-life" show that the screening rate is much lower and PA remains an under-diagnosed and under-treated cause of secondary hypertension with an associated increased risk of cardio- and cerebrovascular mortality and morbidity.

Is There a Role for Genomics in the Management of Hypertension?

Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in Mendelian forms of HTN and the associated pathophysiological mechanisms have been unravelled, leading to targeted therapies. The majority of these syndromes are due to gain-of-function or loss-of-functions mutations, resulting in an alteration of mineralocorticoid, glucocorticoid, or sympathetic pathways. The diagnosis of monogenic forms of HTN has limited practical implications on the population and a systematic genetic screening is not justifiable. Genome-wide linkage and association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), which influence BP. Forty-three variants have been described with each SNP affecting systolic and diastolic BP by 1.0 and 0.5 mmHg, respectively. Taken together Mendelian inheritance and all GWAS-identified HTN-associated variants explain 2-3% of BP variance. Epigenetic modifications, such as DNA methylation, histone modification and non-coding RNAs, have become increasingly recognized as important players in BP regulation and may justify a further part of missing heritability. In this review, we will discuss how genetics and genomics may assist clinicians in managing patients with HTN.

Subtype Diagnosis of Primary Aldosteronism: Is Adrenal Vein Sampling Always Necessary?

Aldosterone producing adenoma and bilateral adrenal hyperplasia are the two most common subtypes of primary aldosteronism (PA) that require targeted and distinct therapeutic approaches: unilateral adrenalectomy or lifelong medical therapy with mineralocorticoid receptor antagonists. According to the 2016 Endocrine Society Guideline, adrenal venous sampling (AVS) is the gold standard test to distinguish between unilateral and bilateral aldosterone overproduction and therefore, to safely refer patients with PA to surgery. Despite significant advances in the optimization of the AVS procedure and the interpretation of hormonal data, a standardized protocol across centers is still lacking. Alternative methods are sought to either localize an aldosterone producing adenoma or to predict the presence of unilateral disease and thereby substantially reduce the number of patients with PA who proceed to AVS. In this review, we summarize the recent advances in subtyping PA for the diagnosis of unilateral and bilateral disease. We focus on the developments in the AVS procedure, the interpretation criteria, and comparisons of the performance of AVS with the alternative methods that are currently available.

The role of autonomic dysfunction in cirrhotic patients before and after liver transplantation. Review of the literature.

In patients affected by hepatic cirrhosis, autonomic dysfunction is a common finding; usually it is asymptomatic but it may correlate with increased mortality and morbidity before, during and after liver transplant, due to hemodynamic instability in the course of stressful events like sepsis, gastrointestinal bleeding and reperfusion after transplantation surgery. Hyperdynamic circulation and hepatic dysfunction seem to play a role in the pathogenesis of autonomic dysfunction, even if pathophysiological mechanisms are not completely known. We present a revision of previous literature about prevalence, pathophysiological mechanisms, clinical features, and mortality and morbidity of autonomic dysfunction secondary to hepatic cirrhosis.

Evaluation of a short home blood pressure measurement in an outpatient population of hypertensives.

Current guidelines suggest the use of home blood pressure monitoring (HBPM) as a method complementary to ambulatory blood pressure monitoring (ABPM) for the identification of arterial hypertension. A cross-sectional study was conducted to evaluate the accuracy of a short HBPM schedule compared with ABPM, and to evaluate to what extent HBPM can replace ABPM. A total of 310 patients who performed ABPM in our hypertension clinic were enrolled between November 2011 and June 2015. They performed a 4-day HBPM schedule, with two readings in the morning and two readings at night. Results showed a moderate correlation between HBPM and ABPM (r = 0.59 for systolic blood pressure (SBP) and r = 0.72 for diastolic blood pressure (DBP)) and moderate diagnostic agreement (area under curve: 0.791 for SBP and 0.857 for DBP). No significant difference was found between first-day average and those of days 2-4. Diagnostic agreement between the two techniques was moderate, supporting the notion that HBPM cannot replace ABPM in the general population. However, we identified two HBPM thresholds, 123/75 and 144/87 mm Hg, through which subjects who may not require further ABPM can be identified.

THE STORM (acute coronary Syndrome in paTients end Of life and Risk assesMent) study.

INTRODUCTION: Elderly patients with coexisting frailty and multiple comorbidities frequently present to the emergency department (ED). Because non-cardiovascular comorbidities and declining health status may affect their life expectancy, management of these patients should start in the ED. This study evaluated the role of Gold Standards Framework (GSF) criteria for identifying patients with acute coronary syndromes (ACS) approaching end of life. METHODS: All consecutive patients admitted to the ED and hospitalised with a diagnosis of ACS between May 2012 and July 2012 were included. According to GSF criteria, patients were labelled as positive GSF status when they met at least one general criterion and two heart disease criteria; furthermore, traditional cardiovascular risk scores (the Global Registry for Acute Coronary Events (GRACE) score and the Age, Creatinine and Ejection Fraction (ACEF) score) were calculated and WHOQOL-BREF was assessed. Mortality and repeat hospitalisation due to cardiovascular and non-cardiovascular causes were evaluated at 3-month and 12-month follow-up. RESULTS: From a total of 156 patients with ACS enrolled, 22 (14%) had a positive GSF. A positive GSF was associated with higher rate of non-cardiovascular events (22.7% vs 6.7%; p=0.03) at 3 months and higher rates of both cardiovascular and non-cardiovascular events (36% vs 16.4%; p=0.04 and 27.3% vs 6.7%; p=0.009, respectively) at 12 months. In multivariate analysis, an in-hospital GRACE score was a predictor of cardiovascular events, while a positive GSF independently predicted non-cardiovascular events. CONCLUSIONS: The GSF score independently predicts non-cardiovascular events in patients presenting with ACS and may be used along with traditional cardiovascular risk scores in choosing wisely the most appropriate treatment. The present results need to be externally validated on larger samples.

Cardiovascular complications in patients with autonomic failure.

Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure.

Arterial hypertension and cancer.

Arterial hypertension and cancer are two of the most important causes of mortality in the world; correlations between these two clinical entities are complex and various. Cancer therapy using old (e.g., mitotic spindle poisons) as well as new (e.g., monoclonal antibody) drugs may cause arterial hypertension through different mechanisms; sometimes the increase of blood pressure levels may be responsible for chemotherapy withdrawal. Among newer cancer therapies, drugs interacting with the VEGF (vascular endothelial growth factors) pathways are the most frequently involved in hypertension development. However, many retrospective studies have suggested a relationship between antihypertensive treatment and risk of cancer, raising vast public concern. The purposes of this brief review have then been to analyse the role of chemotherapy in the pathogenesis of hypertension, to summarize the general rules of arterial hypertension management in this field and finally to evaluate the effects of antihypertensive therapy on cancer disease.

Arrhythmic syncope in neurogenic orthostatic hypotension: two case reports.

Patients with autonomic failure experience orthostatic hypotension (OH) often leading to syncope. Arrhythmias may cause severe syncope, characterized by an increased risk of mortality. We report two cases of patients with primary autonomic neuropathy suffering from both severe OH and arrhythmic syncope.