Fractals in Clinical Hemodynamics

sponsorship: The European Union (HEALTH-F7-2011-278249 EU-MASCARA, HEALTH-F7-305507 HOMAGE and the European Research Council Advanced Researcher Grant 294713 EPLORE) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.0880.13) currently support the Studies Coordinating Centre (Leuven, Belgium). (European Union|HEALTH-F7-2011-278249 EU-MASCARA, European Union|HEALTH-F7-305507 HOMAGE, European Union (European Research Council)|294713 EPLORE, Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium|G.0881.13, Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium|G.0880.13)

Hypertension is highly prevalent in the United States and worldwide. In the United States, 1 in 3 adults (≈73 million people) have hypertension. The financial and human costs of hypertension are substantial. The estimated costs attributable to hypertension in the United States alone in 2010 were $70 billion direct costs for medical treatments and $24 billion indirect costs because of lost productivity.1 Awareness and treatment of hypertension have improved considerably during the past several decades: >80% of all people with hypertension are aware of the condition and 75% are using antihypertensive medications.2,3 However, despite enormous effort and treatment-related expenditures, only 53% of those with documented hypertension have their blood pressure controlled.3 Older age (Figure 1), left ventricular hypertrophy, and obesity are important risk factors for uncontrolled or drug-resistant hypertension.4 Importantly, the foregoing are also risk factors for increased aortic stiffness.5 Figure 1. Hypertension prevalence and control rates as a function of age in the National Health and Nutrition Examination Survey 2003 to 2004. Data derived from Wong et al.44 During the past 2 decades, measures of aortic stiffness have emerged as important risk factors for progression of blood pressure and incident cardiovascular disease. Carotid femoral pulse wave velocity (CFPWV), a measure of aortic wall stiffness, increases markedly with age, particularly after midlife. For example, Framingham Heart Study investigators have shown that the prevalence of CFPWV ≥12 m/s increases from a few percentage before 50 years of age to ≥60% after 70 years of age (Figure 2A). Importantly, elevated CFPWV is associated with high risk for incident hypertension (Figure 2B) and cardiovascular disease (Figure 2C). Figure 2C should be interpreted within the context that a normal value (<95th percentile) for CFPWV in a healthy Framingham Heart Study reference sample <50 years of age was 8.1 …

The current definition of sinus tachycardia is a heart rate >100 beats per minute (bpm).1 This limit was set arbitrarily when heart rate was not yet regarded as a risk factor for cardiovascular disease, probably with the main purpose of distinguishing between a disease state (fever, thyrotoxicosis, anemia, congestive heart failure, etc) and a normal condition. In recent years, interest has been aroused by the awareness that fast heart rate is a potent precursor of hypertension, atherosclerosis, and their sequelae.2 3 4 5 6 7 8 9 10 In addition, many leading epidemiological studies have shown that tachycardia is associated with an increased risk of death from cardiovascular and noncardiovascular causes. This relationship has been found in general populations,3 4 5 6 7 in elderly individuals,9 and in hypertensive cohorts.10 In all of these studies, the heart rate value above that in which a significant increase in risk was observed was below the 100 bpm threshold (Table 1⇓). Only in the study by Levy et al3 was tachycardia defined as a heart rate >99 bpm, but in that study the cutoff between normal and high heart rate was chosen arbitrarily, and the highest heart rate value measured during the examination was taken to define the subject’s heart rate. In all the other studies, the threshold level between normal and fast heart rate was between 79 and 90 bpm. View this table: Table 1. Heart Rate Values Above Which a Significant Increase in Risk Was Found: Data From 9 Epidemiological Studies The normalcy limits of a clinical variable can be established according to different criteria. For many parameters, such as most biochemical indexes, the 95% confidence interval is calculated to identify the upper normal limit of the variable. This statistical approach does not appear suitable for those clinical variables …

Sympathetic traffic to the peripheral vasculature and sympathetic discharge to the heart have complementary effects on blood pressure. Although faster heart rates have been linked to higher blood pressures, the relationship between muscle sympathetic nerve activity (MSNA) and long-term regulation of blood pressure is not clear. We tested the hypothesis that MSNA and heart rate are linked to blood pressure levels in normotensive subjects. We studied normal young male (n=120) and female (n=48) subjects subdivided according to tertiles of heart rate and MSNA distributions. Systolic, diastolic, and pulse pressures were significantly different across the heart rate tertiles in male subjects, with the highest blood pressure values in the upper tertile of heart rate. No significant differences in blood pressure across the tertiles of MSNA were found. The relationship between MSNA and blood pressure, however, was affected by heart rate. MSNA did not influence blood pressure in the first and second heart rate tertiles. However, within the upper heart rate tertile, subjects with higher levels of MSNA had significantly higher systolic (P=0. 02) and pulse (P=0.004) pressures than subjects with lower levels of MSNA. In female subjects, blood pressure was not different across the tertiles of heart rate or MSNA. MSNA and heart rate have interactive effects on systolic blood pressure and pulse pressure in normotensive male but not female subjects. No relationship between MSNA and blood pressure or pulse pressure is evident in subjects with slower heart rate. In male subjects with faster heart rates, higher levels of MSNA are associated with higher systolic and pulse pressures.

Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients With Asymptomatic Hypertension in the Emergency Department

### Case A 68-year-old right-hand-dominant man was brought to the hospital because of a speech disturbance and right arm and leg weakness. He awoke with these deficits and was last known to be symptom-free when retiring to bed the previous evening 8 hours earlier. His past medical history was notable for coronary heart disease, the patient having underwent coronary artery bypass surgery 7 years previously for unstable angina, but he had no known history of myocardial infarction. He also had hypertension and hyperlipidemia, and smoked 1 pack of cigarettes daily for more than 40 years. He had no history of calf claudication. His hypertension was being treated with a diuretic and β-adrenergic receptor blocker. He was also prescribed 325 mg of aspirin daily and an HMG CoA-reductase inhibitor (statin); however, his wife remarked that he often forgot to take his medications. His last total cholesterol was 240 mg/dL, with LDL cholesterol of 130 mg/dL. He had a strong family history of coronary heart disease after the age of 50. He had no known drug allergies. #### Physical Examination The patient’s blood pressure was 195/100 mm Hg in both arms, with a regular pulse of 90 bpm. His weight was 225 lb (body mass index: 31.4 kg/m2). His lungs were clear to auscultation. Cardiac examination showed a laterally displaced point of maximum impulse with an S4 gallop and a soft nonradiating systolic murmur at the base. His abdomen was obese without organomegaly and no abdominal bruits were detected. He had no rashes and no joint deformities. The left superficial temporal artery pulse was stronger than the right. There were soft bilateral anterior cervical bruits, left louder than right, but no supraclavicular bruits. There were bilateral femoral bruits. Radial pulses were 2+ and symmetric. Dorsalis pedis and posterior tibial pulses were 1+. …

Working Group on Blood Pressure Monitoring of the European Society of Hypertension International Protocol for validation of blood pressure measuring devices in adults Eoin O’Brien,Thomas Pickering, Roland Asmar, Martin Myers, Gianfranco Parati, Jan Staessen, Thomas Mengden, Yutaka Imai, Bernard Waeber and Paolo Palatini and with the statistical assistance of Neil Atkins and William Gerin, on behalf of the Working Group on Blood Pressure Monitoring of the European Society of Hypertension

Introduction For practical reasons, blood pressure values measured by physicians or nurses in a medical environment remain the clinical basis of the diagnosis and management of arterial hypertension around the world as recommended by all guidelines [1–4]. Nevertheless, measurements of blood pressure outside the office have gained an increasing popularity over the last decades not only to ascertain the diagnosis of hypertension but also to follow the impact of therapeutic interventions. Out-of-office blood pressure measurements can be obtained either by 24-h ambulatory blood pressure monitoring or by home blood pressure monitoring. As reviewed recently [5], both sets of out-of-office blood pressure offer undeniable advantages when compared to office blood pressure. First, both ambulatory blood pressure and home blood pressure monitoring provide more reliable and reproducible information on blood pressure. Second, blood pressure values obtained by ambulatory blood pressure and home blood pressure monitoring appear to be more closely related to target organ damage than office blood pressure and hence have a greater prognostic relevance than office blood pressure. Third, certain diagnosis such as white coat hypertension and masked hypertension can only be diagnosed using out-of-office blood pressure measurements. Fourth, when used in the clinical follow-up of treated hypertensive patients to evaluate the impact of drug treatment, ambulatory blood pressure monitoring as well as home blood pressure monitoring has the advantage of not being affected by a placebo effect. Finally, evidence has been provided that treatment-induced reduction in 24-h blood pressure may predict better than office blood pressure the regression of end organ damage (particularly the cardiac one) induced by antihypertensive drug. Many of these information have been achieved during the past two decades by a number of studies carried out in different populations around the world, including the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study [6–10]. When should out-office blood pressure be measured? Despite their advantages, ambulatory blood pressure monitoring as well as home blood pressure monitoring is not regarded as a routine procedure that should be applied to all hypertensive patients essentially for economical reasons. However, this issue is debated because the clinical information gathered with these measurements may potentially result in financial savings when applied adequately. The European and American guidelines for the management of hypertension have defined some indications for the use of ambulatory blood pressure monitoring in hypertension [1,2]. These include patients with resistant hypertension, patients with a high variability of office blood pressure, low-risk patients with a high blood pressure, patients with suspected episodes of hypotension, patients with a large discrepancy between office and home blood pressures, and finally patients with special clinical conditions such as pregnancy or sleep apnea syndrome. Outside these indications, the use of ambulatory blood pressure monitoring could be discussed both in terms of feasibility and economics. Theoretically, a measurement of out-of-office blood pressure could be recommended to all new patients with as suspected hypertension to confirm the diagnosis of hypertension and to refine the patient's cardiovascular risk profile. Therefore, ambulatory blood pressure monitoring could be recommended to all high cardiovascular risk patients before starting any treatment and later under therapy to ascertain the adequacy of the control of blood pressure. Ambulatory blood pressure values in diabetic patients In this issue of the Journal of Hypertension, Leitao et al.[11] report the results of a cross-sectional study performed to estimate the daytime ambulatory blood pressure monitoring values corresponding to the target office blood pressure of 130/80 mmHg for diabetic (as defined by the American Diabetes Association) and to assess which diabetic patients may actually benefit from ambulatory blood pressure monitoring. They included 554 patients in this analysis. Regression analyses were performed to analyze the ambulatory blood pressure monitoring values corresponding to office blood pressure and receiver operating characteristics (ROC) curves were used to assess the sensitivity and specificity of office blood pressure in diagnosing daytime ambulatory blood pressure monitoring hypertension. According to their regression equations, the daytime ambulatory blood pressure monitoring corresponding to the target office blood pressure of 130/80 mmHg was 129/79 mmHg and the daytime ambulatory blood pressure monitoring value corresponding to 140/90 mmHg at the office was 134/82 mmHg. As expected, discrepancies between ambulatory blood pressure monitoring and office blood pressure were due essentially to masked hypertension (about 10% of cases) and white coat hypertension (between 19% for systolic blood pressure and 26% for diastolic blood pressure). Interestingly, when office blood pressure was lower than 120 mmHg systolic and 70 mmHg diastolic, the sensitivity to rule out hypertension using ambulatory blood pressure monitoring was 90%. Similarly, when office blood pressure was more than 145 mmHg systolic and more than 90 mmHg diastolic the sensitivity to confirm hypertension using ambulatory blood pressure monitoring was 90%. Within these two sets of limits, 38% of patients would be misclassified if only office blood pressure values would be considered for the diagnosis. Thus, using the cut-off values of less than 120/70 mmHg and more than 140/90 mmHg at the office, 56% of the population sample would need an ambulatory blood pressure monitoring to confirm the diagnosis of hypertension. According to these results, only diabetics with an office blood pressure between 120 and 140 mmHg systolic and/or a diastolic blood pressure between 70 and 90 mmHg would really benefit from an out-office assessment of blood pressure. This would limit the use of ambulatory blood pressure monitoring to only 50% of the diabetic patients. Studies implications and limitations The results of this provide interesting practical information on the use of ambulatory blood pressure monitoring in diabetic patients. However, they also have some limitations. The first one is the fact that the entire analysis is based on daytime ambulatory blood pressure only. Although the authors have measured 24-h blood pressure, they have not considered the nighttime blood pressure. This is unfortunate because there is increasing evidence that nighttime is a better predictor of cardiovascular risk than daytime blood pressure. Moreover, diabetic patients are often characterized by an absence of the physiological fall in blood pressure reflecting a nondipping pattern at night. Diabetes may even be the cause of a reverse dipping, that is an increase in blood pressure at night. Both the nondipping and the reverse dipping pattern of blood pressure have been associated with an increased risk of developing target organ damages such as left ventricular hypertrophy, microalbuminuria, renal dysfunction, and cerebral vascular lesions [5,12]. Thus, when assessing the cardiovascular risk profile linked to hypertension in diabetic patients, nighttime blood pressure should be included. Indeed, it is not uncommon in diabetes that daytime normotensive patients exhibit a nocturnal hypertension. This type of patients would be misdiagnosed using the algorithm proposed by the authors. Recently, the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial have shown that in diabetic patients the reduction of cardiovascular morbidity and mortality obtained by lowering office blood pressure below 120 mmHg systolic is not greater than that seen reducing blood pressure below 130 mmHg [13]. On the contrary, a systolic blood pressure below 120 mmHg may result in an increased risk of developing cardiac complications, as suggested by the recent post hoc analysis of diabetic patients with coronary heart diseases having participated in the INternational VErapamil SR-Trandolapril (INVEST) Study [14]. If a low blood pressure increases the risk of cardiac complications in diabetics, one might have to reconsider the necessity to perform an ambulatory blood pressure monitoring in diabetic patients with a blood pressure <120/70 mmHg in contrast to the proposals of Leitao et al. Indeed, in treated diabetic patients with a low office blood pressure, ambulatory blood pressure monitoring could be of importance to diagnosis episodes of asymptomatic hypotension episodes which might increase their cardiac risk. Thus, in the analysis of daytime and nighttime blood pressure values, it would be of interest to assess whether the percentage of ambulatory blood pressure values below a certain level is indeed associated with an increased risk of some cardiovascular complications. In this respect, it is important to mention that the analysis presented by Leitao et al. does not provide any information on the presence in this particular patients population of cardiac organ damage. The study also does not provide any data such on the occurrence of cardiovascular events and deaths, as it was not a prospective cohort study. Both these two sets of information should be thus provided by future clinical trials.

Hypertension Optimal Treatment (HOT) trial

The increasing use of ambulatory blood pressure monitoring (ABPM) devices in the investigation of hypertension has allowed detailed study of the circadian rhythm of blood pressure variability, the assessment of resistant hypertension, and the syndrome of “white coat” hypertension. The relevance of ABPM to target-organ damage and the complications of hypertension, such as heart attacks and strokes, has only recently gained prominence. There are more than 30 cross-sectional studies that have linked ABPM to hypertensive target-organ damage, including left ventricular hypertrophy (LVH),1 2 microalbuminuria,3 hypertensive retinal changes, and cerebrovascular disease.4 The majority of these studies have consistently reported that patients with an absent or reduced fall in blood pressure at night (referred to as “nondippers”) have more severe target-organ damage, including LVH5 and cerebrovascular disease,4 6 when compared with patients who demonstrate a normal nocturnal fall in blood pressure. For example, Verdecchia et al,7 in a prospective cohort of over 1100 hypertensive patients, reported higher mortality rates both in nondippers and “reverse dippers” and higher cardiovascular morbidity rates in female nondippers compared with dippers.8 In addition, Yamamoto et al9 recently reported that progressive cerebrovascular disease, including silent ischemic lesions and symptomatic stroke, was associated with a reduced nocturnal blood pressure fall in patients with a history of lacunar infarction. In a cross-sectional study of patients admitted with acute stroke (ictus <12 hours), Lip at al10 reported that such patients could generally be classed as nondippers, with higher blood pressures recorded using ABPM (but not using casual manual measurements) in black/Afro-Caribbean patients and also in patients with hemorrhagic stroke. These studies therefore suggest the potential usefulness of ABPM in epidemiological, cohort, or cross-sectional studies and the assessment of ethnic differences, stroke subtypes, and prognosis. A nondipper status …

Arterial muscle sympathetic baroreflexes are frequently assessed using pharmacologically evoked decrements in arterial blood pressure. Since drugs administered for baroreflex tests may themselves alter the sympathetic response to evoked pressure variations we proposed a method to determine sympathetic baroreflex gain during spontaneous fluctuations in arterial pressure at rest and tested the null hypothesis that baroreflex gain assessed during spontaneous fluctuations in arterial pressure equals baroreflex gain determined during evoked hypotension. Muscle sympathetic nerve activity (MSA), arterial blood pressure, and heart rate were assessed at rest in 15 healthy volunteers (age: 29 years +/- 5, mean +/- SD). All diastolic pressures sampled during a 5 min period were grouped in intervals of 1 mmHg and the burst incidence per interval was calculated. The slope of the regression line of burst incidence and diastolic pressure represents baroreflex gain during spontaneous fluctuations in arterial pressure. In the same volunteers, burst incidence was also determined over 30 s periods before and after a decrease in arterial pressure evoked by nitroprusside (SNP, 2-3 micro g kg(-1) i. v.). The relationship between mean MSA burst incidence and diastolic arterial pressure was compared before and after the pressure decrease yielding an average baroreflex "gain" during evoked hypotension. Average baroreflex "gain" assessed by this conventional method was compared to baroreflex gain assessed during spontaneous arterial pressure fluctuations by Bland-Altman analysis and correlation analysis. Resting MSA was 28 bursts/100 heart beats +/- 10 at a diastolic pressure of 71 mmHg +/- 11. Baroreflex gain during spontaneous arterial pressure fluctuations was 4.0% mmHg(-1) +/- 1.9 and was significantly greater than the average "gain" assessed during evoked hypotension (2.1% mmHg(-1) +/- 1.6). Individual values for baroreflex gain determined with both methods did not correlate (r = 0.1, p = 0.8). Baroreflex gain as determined during spontaneous arterial pressure fluctuations differs from that assessed during SNP-evoked hypotension, possibly due to intrinsic effects of SNP on the baroreflex. Thus, caution should be exercised when interpreting baroreflex gain derived during SNP-evoked hypotension.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

1. The magnitude and time course of circulatory adaptation to active standing were investigated in healthy premenarchic girls and boys (n = 24; 10-14 years old) by non-invasive measurement of heart rate and continuous finger blood pressure (Finapres). 2. Four subjects (two girls, two boys) showed presyncopal symptoms after 4-9 min of free standing. 3. In the 20 non-fainting subjects, changes in blood pressure and heart rate upon standing did not differ between girls (n = 10) and boys (n = 10). In the initial phase of standing (first 30 s) systolic and diastolic blood pressures dropped by 22 +/- 14 (mean +/- SD) and 16 +/- 7 mmHg, respectively, at 8 +/- 2 s. Blood pressure subsequently recovered and showed an overshoot in all subjects. The transient drop in blood pressure was accompanied by an increase in heart rate of 40 +/- 7 beats/min. These characteristic transient changes were not observed with passive head-up tilt. During the early steady-state phase (2 min), systolic blood pressure was similar to the supine value and diastolic blood pressure rose by 11 +/- 5 mmHg. Heart rate increased by 25 +/- 11 beats/min. In six of the subjects (three girls, three boys) the increase in heart rate exceeded 30 beats/min (postural tachycardia). Little further changes were observed during prolonged (10 min) standing.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct measurements of systolic, diastolic, and mean arterial blood pressure and electrocardiogram-derived heart rates were compared with indirect arterial blood pressure measurements using the Dinamap 847XT noninvasive monitor. A total of 260 paired comparisons from 16 patients were analyzed. A regression analysis of paired data over a wide range of blood pressure values gave the following results: for heart rate r = 0.97, for systolic arterial pressure r = 0.84, for mean arterial pressure r = 0.73, and for diastolic arterial pressure r = 0.52. The 95% confidence limits for systolic, mean, and diastolic arterial pressure were +/- 16 mm Hg, +/- 18 mm Hg, and +/- 21 mm Hg, respectively. The Dinamap monitor was found to be an accurate trend recorder of heart rate and blood pressure during anesthesia in neonates and small infants.

Background and Aims Increase in resting heart rate might influence mortalities of dialysis patients, and the use of β-blocker might improve their survival probability. However, the influence of heart rate and benefits of β-blocker on their survival are difficult to quantify because of following obstacles: prone to measurement errors; inherent association of heart rate with blood pressures, comorbidities, and medication use; and a necessity of repeated measurements of vital signs and medication use. Therefore, at the design process of our previous randomized control trial on the Olmesartan Clinical Trial in Okinawan patients under OKIDS (OCTOPUS), we included the repeated measures design to quantify the influence of vital sign values on the survival retrospectively. We combined the repeated measurement data and additional the long-term prognosis information of the participants obtained after the OCTOPUS with aim of investigating the influence of time varying covariates: heart rates, blood pressures, and β-blocker use, on the long-term survival of hemodialysis patients. Method We investigated 461 adult OCTOPUS participants who received chronic hemodialysis and antihypertensive medications in Okinawa. The OCTOPUS trial, which was conducted between June 2006 and June 2011, did not detect the survival benefit of angiotensin receptor blocker (ARB)NDT 2013, but the study and the additional follow-up of participants’ prognosis provided us with information to investigate influence of predictors on long-term survival in the population. Throughout the OCTOPUS trial, study participants were measured pre-dialysis blood pressures, pre-dialysis resting heart rates, and their medication use for one week at their dialysis centers every six months after their participations. Following the trial, we collected the prognosis information of all participants until July 31st, 2018. Finally, we merged the multiple-measured data during the OCTOPUS with the prognosis data. Mean values of three measurements of blood pressures and heart rates and β-blocker use were introduced to the Cox-regression model as time-varying covariates with essential non-time varying covariates, which include age, gender, and diabetes. Results In this retrospective cohort study, 221 (47.9%) out of 461 participants deceased, and the median follow-up length was 10.21 years. Initial mean resting heart rate and pre-dialysis mean blood pressure were 78(±10) per minute and 159.5(±14) mmHg, respectively. 10% of participants were prescribed β-blocker initially. The resting heart rate of all participants significantly decreased by 1.75 and 2.45 per minutes after two and four years respectively. β-blocker could significantly decrease the mean heart rate by 3.54 and 2.90 per minutes after two and four years. With our Cox-regression with the time varying covariates, increase of heart rate was significantly associated with higher mortality (P=0.002), but the use of β-blocker was not associated with the mortality. (P=0.691) Additionally, we could not detect the interaction of heart rate and β-blocker use on the mortality. (P= 0.796) Although lower blood pressure was significantly associated with higher mortality in our initial Cox-regression analysis, an introduction of interaction term of heart rate and blood pressure remove the significance of influence of blood pressure on the survival. Conclusion In hypertensive chronic hemodialysis patients, higher heart rate is associated with higher mortality. However, use of beta-blocker was not associated with improvement of their mortality.