Information

How does noradrenaline result in rise of systolic blood pressure even when the cardiac output is decreasing?


Systolic blood pressure[SBP] depends on the cardiac output. When Nor adrenaline is given there is vasoconstriction due to alpha-1 action on blood vessel, vasoconstriction results in increased total peripheral resistance and thus increases the diastolic blood pressure. The beta-1 action [increase in cardiac output] on heart by Nor adrenaline is counteracted by the reflex bradycardia resulting in decreased cardiac output. Given the fact that SBP depends on cardiac output and the cardiac output is decreasing, why is there a rise in SBP on administering nor adrenaline?


Your question involves comparing an observed response to administration of noradrenaline/norepinephrine, which causes vasoconstriction thereby increasing the BP (during both systole & diastole,) to the hemodynamic/pharmacodynamic response of the cardiovascular system as a whole, which is decreased cardiac output & decreased cardiac work. This is similar to asking why opening a finite water tank eventually slows down even though the pressure increases when you turn on the faucet.


The sympathetic nervous system and blood pressure in humans: individualized patterns of regulation and their implications

The autonomic nervous system and its sympathetic arm play important roles in the regulation of blood pressure. 1 , 2 , 3 Their role in the short-term regulation of blood pressure, especially in responses to transient changes in arterial pressure, via baroreflex mechanisms is well known. 4 However, the role of the sympathetic branch in longer term (days, months, years) blood pressure regulation has been a focus of debate since at least the 1970s. 1 , 4 Our goal in this “Hypertension Highlights” is to summarize and integrate our ideas on the role of the sympathetic nervous system in long-term blood pressure regulation in humans. 1 , 2 , 3 , 5 , 6 , 7 , 8 , 9 We will focus primarily on information from studies conducted in humans and use data from animal studies to emphasize key points. In this context, we want to address four key questions. The first three focus on our recent work. The final issue is an emerging one and more speculative.

What is the role of the sympathetic nervous system in long-term blood pressure regulation in young (18� year old) normotensive men?

Does the role of the sympathetic nervous system in long-term blood pressure regulation change as a function of age in men?

Does sex influence the role of the sympathetic nervous system in long-term blood pressure regulation, and are sex differences modified by aging?

Are we entering an era of sympathetically driven hypertension?

Before we address these questions, a few thoughts about how to assess the overall activity of sympathetic nerves in humans.

Assessment of sympathetic activity in humans

Various approaches used to assess sympathetic activity in humans have recently been reviewed by Grassi. 10 We focus primarily on studies that use direct measurements of muscle sympathetic nerve activity (MSNA) as an overall marker of sympathetic outflow in humans and to a lesser extent on studies use whole body and regional norepinephrine spillover, and also plasma norepinephrine (NE). There are advantages and disadvantages with each of these approaches that have been reviewed in detail. 2 , 10

In resting humans these three approaches are typically well-correlated, and conclusions made with one technique are generally supported by studies using one of the other two approaches. 11 , 12 , 13 , 14 There are two major caveats to this point. First, the correlations between MSNA and other indices of sympathetic activity have been most clearly demonstrated in young healthy men. 11 Second, during non-resting conditions (e.g., exercise, mental stress etc.) there can be highly specific changes in sympathetic activity to selected tissues with no changes in other tissues. For example, MSNA following arousal stimuli (such as startling the subject with a loud noise) either does not change or falls for a few bursts in some subjects, and MSNA can fall during mental stress. 15 , 16 , 17 , 18 However, skin sympathetic activity (SSNA) increases during both arousal and mental stress. 19 SSNA also increases at the onset of static exercise before any rise in MSNA. 20

MSNA as an index of overall sympathetic activity in resting young men has a number of attractive features

Most of the studies from our laboratories and those of many colleagues have used MSNA as the primary index of sympathetic activity in humans. MSNA is a direct measure of vasoconstrictor neural activity to skeletal muscle, a vascular bed whose sheer size and makes it central to hemodynamic control both at rest and during daily activities. MSNA is also reproducible in a given subject over time. 21 However, MSNA increases with age, such that measurements in a given individual increase after a period of several years 21 , 22 . As noted above, MSNA also correlates well with other markers of sympathetic neural activity at rest, at least in young men. Most importantly from our perspective, measurements of MSNA can be combined with other hemodynamic measurements to paint an overall picture of the relationship between sympathetic neural activity and blood pressure regulation. Additionally, because it has both rapid time resolution and is also stable within a given subject from day to day, MSNA can be used to address questions about both short and long term blood pressure regulation.

What is the role of the sympathetic nervous system in long term blood pressure regulation in young normotensive men?

In normotensive young men MSNA measured during rest can vary 5- to 10-fold, and there is substantial overlap in the range of MSNA values seen in normotensive and hypertensive subjects. 3 , 5 , 13 , 23 , 24 , 25 This observation would seem to be a powerful argument against a major role for the sympathetic nervous system in long-term blood pressure regulation. For example, if MSNA can be very low in one individual, and very high in another an individual with a similar blood pressures, then how can MSNA be important to blood pressure regulation? This variability was also frustrating to those who developed the technique and hoped to use it to diagnose sympathetically driven hypertension. 19 However, it has become clear in recent years that the striking inter-individual variability in MSNA provides mechanistic information about the role of the sympathetic nervous system in long term blood pressure regulation. In this context, why isn’t MSNA more directly related to blood pressure?

Our initial hypothesis was that in normotensive subjects with high levels of baseline MSNA, a relatively low value for cardiac output (CO) would offset the influence of higher sympathetic nerve activity and vascular resistance (i.e., MAP = CO x TPR) on blood pressure. To test this hypothesis, we conducted studies in healthy young men to understand how normotension is maintained in subjects with a range of sympathetic activities. 5 , 6 , 7 , 8 , 9 Our main findings (summarized in Figure 1 ) are that in young men there is an inverse relationship between MSNA and cardiac output.

Panel A demonstrates the relationship between muscle sympathetic nerve activity (MSNA) and mean arterial pressure in a group of young healthy males. Panel B demonstrates the reciprocal relationship between MSNA and cardiac output in the subjects. This relationship helps explain why blood pressure is not consistently higher in subjects with high levels of MSNA. (Figure from ref 5 )

This means that subjects with high levels of MSNA have lower cardiac outputs and vice versa. At first we were surprised by the range of cardiac outputs we observed, but review of the literature indicated that the values we observed were similar to those found using invasive techniques by Julius and Conway in their classic paper from 1968. 26

Importantly we also found that in young men total peripheral resistance (TPR) is highly correlated with resting MSNA. 5 This observation is also consistent with studies in men showing that fall in blood pressure seen during ganglionic blockade with trimethaphan (so-called 𠇊utonomic support” of blood pressure) is proportional to resting MSNA and plasma NE concentrations. 14

Next we demonstrated that the impact of high levels of MSNA on blood pressure in young men is blunted by reduced vasoconstrictor responsiveness to NE. 7 Whether the inverse relationship between baseline MSNA and adrenergic sensitivity reflects receptor down regulation in response to high MSNA, or whether high levels of MSNA are a compensatory response to low number or responsiveness of post-junctional receptors is not known. If the former were responsible for the inverse relationship between MSNA and adrenergic sensitivity, this would suggest that baroreflex control of MSNA might be blunted in subjects with high levels of MSNA. In the latter case, it would suggest that the high levels of MSNA were an appropriate baroreflex-mediated response to an inherently lower level of adrenergic receptors.

Another aspect of our original hypothesis regarding inter-individual variability in MSNA was that the absence of a relationship between MSNA and blood pressure in young men was due to tonic NO release from the vascular endothelium. The idea was that NO release (and subsequent vasodilation) proportional to the level of sympathetic activity offsets the vasoconstriction caused by the MSNA. The best evidence for this came from studies showing plasma nitrate levels are correlated with baseline MSNA. 27 To test this hypothesis, we performed systemic dose-response studies with the nitric oxide synthase inhibitor L-NMMA in normotensive volunteers. We found that the rise in BP was greater in subjects with high levels of baseline MSNA. 7 This was especially marked with the lower doses of L-NMMA.

Interestingly, the hemodynamic mechanisms for the greater increase in blood pressure in the high MSNA group were related to cardiac output because total peripheral resistance responses to NOS inhibition were similar between high and low MSNA groups. The high MSNA group had a lower cardiac output to begin with and showed a smaller decline in CO during NOS inhibition. In this context, these data suggest that humans with high levels of baseline MSNA are at higher risk for the development of hypertension if they experience an even modest reduction in endothelial function. A major limitation to this interpretation is that systemic administration of L-NMMA, causes potentially confounding increase in blood pressure and a baroreflex mediated inhibition of MSNA.

An important final point is that the sources or cause of the inter-individual variability in MSNA are unknown. Identical twins demonstrate similar values suggesting a strong genetic component, but neither the physiological nor potential genetic mechanisms responsible for the inter-individual variability in MSNA have been identified. 28

Does the role of the sympathetic nervous system in long term blood pressure regulation change in aging males in the absence of diseases and conditions known to affect blood pressure?

Whole body sympathetic neural activity increases with aging. 9 , 14 , 21 , 22 This is reflected by increases in MSNA, whole body norepinephrine spillover, and increases in plasma norepinephrine levels. 9 , 14 , 29 Additionally, indices of sympathetic activity, especially MSNA, become more linked to blood pressure as a person ages. 25 In general, MSNA increases about one burst per minute per year, starting around age 30 ( Figure 3 ). This means that MSNA in 60� year olds is roughly twice as high as it is in 20� year olds, but a wide range of MSNA is still seen in older subjects.

Relationship between baseline MSNA and mean arterial pressure in a large group of young males, young females, older males and older females. In both men and women 㱀 no relationship between MSNA and mean arterial pressure was seen. By contrast, in the older men there was a modest relationship between MSNA and blood pressure. This positive relationship was more pronounced in the older women. (Figure from ref 25 )

In healthy older subjects free of coexisting disease, there are several possible explanations for the rise in sympathetic activity with aging. First, there might be a loss of central inhibitory pathways in the brainstem. Central sympathetic disinhibition is clearly seen in animal models of diseases like congestive heart failure and but it is unclear if this occurs with healthy older humans without overt cardiovascular disease. 30 , 31 However, there is evidence for increased central NE spillover in aging humans. 32 Second, the large blood vessels become less distensible with aging and this might cause a given level of blood pressure to evoke fewer baroreflex mediated afferent signals and less reflex inhibition of sympathetic outflow. 33 , 34 Third, aging (even in the absence of weight gain), is associated with increases in body fatness and there is evidence that visceral adiposity is associated with increased levels of sympathetic activity. 35 , 36 This might be due to inflammatory mediators or substances released by visceral fat cells that stimulate sympathetic outflow at the level of the central nervous system. 36 However, all of these potential mechanisms are speculative and there is at least some evidence for all of them in humans and animal models.

In spite of the increased sympathetic activity with aging, the relationship between MSNA and blood pressure remains modest in older men. One factor that limits the impact of the increased levels of sympathetic activity on blood pressure is age-related blunting of adrenergic sensitivity. In older men, there is clear evidence in the forearm and leg that vasoconstrictor responsiveness (sensitivity) to adrenergic stimulation is reduced and post-junctional alpha-2 sensitivity appears reduced more than alpha-1 sensitivity. 38 , 39 Additionally, infusions of phenylephrine after ganglionic blockade (to block baroreflex buffering of blood pressure) cause blood pressure to rise about 50% less in older versus younger males. 40

We attempted to study the individual relationships between MSNA, cardiac output and total peripheral resistance in healthy older males to determine if the relationships we saw in younger men were similar or altered in a systematic way with aging. 9 In contrast to younger subjects, we could find no overall pattern of relationships between MSNA, cardiac output, vascular resistance and/or vascular adrenergic responsiveness in older men, indicating that the balances seen in younger men were absent in healthy men. However, it is interesting to note that autonomic support of blood pressure is greater in older males compared to younger males. While some of this is due to a lower intrinsic heart rate in older men, it also suggests that the increase in sympathetic activity is not completely offset by age-related reductions in adrenergic sensitivity. 14 Another possible factor is that healthy older males have reduced blood volume which might lead to a larger fall in blood pressure after ganglionic blockade, and they can also have reduced endothelial function which might further modify the relationships between MSNA, cardiac output and TPR. 41 , 42 Taking into account all available information, we speculate that if aging affects different mechanisms in different subjects, systematic relationships between and among factors are more difficult to detect.

Does sex influence the role of the sympathetic nervous system in long term blood pressure regulation, and are any sex differences modified by aging?

With our observations in men as a background, an important question was whether or not the relationships (or lack thereof) between MSNA, cardiac output, total peripheral resistance, and adrenergic sensitivity are the same or different in women. When we studied young healthy women we again found a wide range of MSNA, but there was no relationship between MSNA and blood pressure. 8 There was also no relationship between MSNA and cardiac output and, most surprisingly, no relationship between MSNA and total peripheral resistance ( Figure 4 ). This suggests that the physiological “strategy” used to regulate blood pressure in young women is fundamentally different from that in young men.

Relationship between MSNA and total peripheral resistance (TPR) in a group of normotensive young male subjects (left panel) and a group of normotensive young female subjects (right panel). The relationship between MSNA and TPR seen in the young men was absent in the young women. (Figure from ref 8 )

Additionally, the lack of relationship between MSNA and TPR in young women is consistent with observations suggesting that autonomic support of blood pressure is lower in young women than young men. 43 Unfortunately, there are no clear data on the relationship between MSNA and autonomic support of blood pressure in young women. 44 However, based on the range of values typically seen in young women, and assuming a relatively normal distribution of MSNA, it is reasonable to speculate that the inter-individual relationship between MSNA and autonomic support of blood pressure are blunted or absent in young women compared to young men.

What might explain the absence of a relationship between MSNA and total peripheral resistance in young women? 8 One explanation is that postjunctional β2 receptors on the vascular smooth muscle and vascular endothelium in younger women are stimulated by norepinephrine and blunt the alpha-adrenergic vasoconstrictor effects of the sympathetic nerves. Indeed, Kneale et al showed that the vasoconstrictor responses to brachial artery infusions of norepinephrine are blunted in young women in comparison to young men. 44 However, when norepinephrine dose-response curves were performed after β-adrenergic blockade with brachial artery administration of propranolol, vasoconstrictor responses to NE were augmented in the women and unchanged in the men. Thus, the forearm vasoconstrictor responses to NE were similar in men and women after propranolol. In this context, β2 vasodilation in the forearm has both an endothelial and non-endothelial component and about 30�% of the vasodilator effects are due to endothelial release of nitric oxide. 45

What is the situation in older women? As is the case for older men, MSNA rises with age and the relationship between MSNA and blood pressure becomes stronger with aging. 25 Additionally, the strength of this relationship is greater in older women than older men ( figure 4 ). However, there is little definitive data on why blood pressure is more strongly related to sympathetic activity in older women than men. This is important because it is well known that the incidence of hypertension rises after menopause in women. 46 However, it is not known if autonomic support of blood pressure is greater in older women than younger women or in their male counterparts. Additionally, there are no data on adrenergic sensitivity in older women and there are no comprehensive measurements of cardiac output and MSNA in older women.

However, it is tempting to speculate that the loss of endothelial function seen post-menopause contributes to the more robust relationship between MSNA and blood pressure in older women. 47 Additionally, if aging is associated with a loss of β2-mediated vasodilator function in women and these receptors normally blunt the relationship between MSNA and vascular resistance in young women, their loss could contribute to the positive relationship between MSNA and blood pressure in older women.

In summary, the relationship between MSNA and blood pressure differs in younger and older women and in comparison to their male counterparts. Understanding these differences may help explain why younger women are more prone to orthostatic intolerance and why older women are more subject to hypertension.

Are we entering an era of sympathetically driven clinical hypertension?

Obesity and weight gain are conditions associated with increased MSNA ( figure 5 ). 36 , 48 , 49 , 50 Obesity is also a major risk factor for Obstructive Sleep Apnea (OSA), and OSA appears associated with increases in both blood pressure and MSNA. 51 , 52 , 53 Additionally, similar results are found when NE spillover techniques are used to assess sympathetic activity in these populations. 59 These factors appear to add to and perhaps amplify any age-related increases in MSNA. They are also associated with increased vascular stiffness and reduced endothelial function which would limit baroreflex buffering of MSNA and NO-mediated buffering of vasoconstriction mediated by MSNA. 1 , 34 , 42 This constellation of conditions, which is increasing in both developed countries and countries with emerging economies, is also associated with physical inactivity and/or metabolic disorders such as type II diabetes and changes in blood lipids. Importantly, these factors would tend to reinforce the changes in MSNA and vascular function highlighted above and lead to higher blood pressure. 1 Additionally, there is evidence suggesting that blood pressure reactivity and chronic mental or social stress is related to the long term risk of hypertension in humans. 54 , 55

Relationship between waist circumference (left panel) or fat mass (right panel) and baseline MSNA in a large group of young and old male subjects. (Figure from ref 36 )

There is also emerging evidence that obese humans with mild hypertension have increased autonomic support of blood pressure. 56 , 57 , 58 This general idea is also supported by the NE spillover data reviewed by Esler and colleagues 59 showing that sympathetic outflow to skeletal muscle and kidney is increased 2𠄳 fold in obese subjects. It is also supported by data from overfeeding studies in dogs showing that suppression of sympathetic neural activity in obese hypertensive animals by prolonged baroreflex stimulation lowers blood pressure, and similar data is emerging in humans with so-called resistant hypertension. 60 , 61

There is also evidence that the increased sympathetic activity seen in resistant hypertension is related in part to the kidney because radiofrequency denervation of the kidney lowers blood pressure in patients with resistant hypertension. 62 In this context, if MSNA reflects renal sympathetic nerve activity (RSNA) then increases in the latter may play a causal role in promoting hypertension by increasing sodium retention by the kidneys. While increases in RSNA would be expected to increase arterial pressure, this might not happen if there were reductions in renal adrenergic vascular responsiveness, increased renal NO production, or other offsetting mechanisms. However, the interactions between the sympathetic nervous system and kidney in the long term regulation of blood pressure in both normotensive and hypertensive humans remains unclear. 63 , 64 , 65

Blood pressure increases with salt loading in rats are amplified by barodenervation arguing for a reinforcing interaction 65 between increased sympathetic outflow and renal sodium retention. By contrast, renal denervation does not blunt the sustained reductions in arterial pressure caused by long term activation of baroreflexes. 63 , 64 Clearly, the interactions and cross-talk between multiple redundant regulatory responses makes it especially challenging to design definitive experiments on this topic in humans. It is also possible that vascular beds that are hard to study with current approaches contribute to the relationship between sympathetic neural outflow and blood pressure. For example the splanchnic bed is a potential volume reservoir and long-term changes in vascular tone in this region could influence blood pressure.

Summary and Future Directions

We have attempted to summarize and highlight key elements of our recent thinking on the role of the sympathetic nervous system in long-term blood pressure regulation in humans. Our goal has been to use the marked inter-individual variability in MSNA seen in humans to begin to explore this topic. In normotensive young men MSNA is proportional to total peripheral resistance but the effects of this relationship on blood pressure are limited by a reciprocal relationship between MSNA and cardiac output and the fact that adrenergic sensitivity is blunted in subjects with high levels of MSNA. In young women these relationships are absent and there is some evidence that β2-adrenergic receptor mediated vasodilation limits the relationship between sympathetic activity and vascular resistance.

In older men the average level of MSNA is increased and modestly related to blood pressure, but there is still wide inter-individual variability in MSNA and no clear relationships between MSNA, cardiac output and vascular resistance. In older women the average level of MSNA is also increased and more strongly related to blood pressure. This suggests that any effect of reproductive hormones and β2- adrenergic receptor mediated vasodilation that limits the impact of high levels of MSNA on vascular resistance in young women is lost with aging. These potential age-related changes in women might explain the accelerated incidence of hypertension after menopause. However, the data on these relationships in women in general and older women in specific is limited, but clearly deserving of additional focus.

When we consider our findings and those of others in the context of emerging demographic trends for conditions like obesity, sleep apnea, physical inactivity and perhaps “social stress” we propose that an era of sympathetically driven hypertension exacerbated by the factors discussed above is here.

Relationship between several indices of sympathetic neural activity and the fall in blood pressure during ganglionic blockade in a combined cohort of young and old males. The left panel shows that individuals with higher baseline levels of MSNA experience a larger fall in blood pressure during ganglionic blockade. The right panel is a similar comparison between the change in blood pressure and plasma norepinephrine (PNE). Together these data show that individuals with high levels of baseline sympathetic activity have increased autonomic support of their blood pressure. (Figure adapted from ref 14 )


Similar to how systemic high blood pressure can cause the heart to work harder to deliver blood to the body, pulmonary hypertension can occur when the arteries in the lungs narrow and thicken, slowing the flow of blood through the pulmonary arteries to the lungs. As a result, the pressure in your arteries rises as your heart works harder to try to force the blood through. Heart failure occurs when the heart becomes too weak to pump enough blood to the lungs.

  • Shortness of breath during routine activity
  • Fatigue
  • Chest pain
  • Racing heartbeat
  • Pain in upper right side of abdomen
  • Decreased appetite
  • Feeling light-headed, especially during physical activity
  • Fainting
  • Swelling in the ankles or legs
  • Bluish lips or skin

Systolic Blood Pressure Response During Exercise Stress Testing: The Henry Ford ExercIse Testing (FIT) Project

The prognostic significance of modest elevations in exercise systolic blood pressure response has not been extensively examined.

Methods and Results

We examined the association between systolic blood pressure response and all‐cause death and incident myocardial infarction (MI) in 44 089 (mean age 53±13 years, 45% female, 26% black) patients who underwent exercise treadmill stress testing from the Henry Ford ExercIse Testing (FIT) Project (1991–2010). Exercise systolic blood pressure response was examined as a categorical variable (>20 mm Hg: referent 1 to 20 mm Hg, and ≤0 mm Hg) and per 1 SD decrease. Cox regression was used to compute hazard ratios (HR) and 95% CI for the association between systolic blood pressure response and all‐cause death and incident MI. Over a median follow‐up of 10 years, a total of 4782 (11%) deaths occurred and over 5.2 years, a total of 1188 (2.7%) MIs occurred. In a Cox regression analysis adjusted for demographics, physical fitness, and cardiovascular risk factors, an increased risk of death was observed with decreasing systolic blood pressure response (>20 mm Hg: HR=1.0, referent 1 to 20 mm Hg: HR=1.13, 95% CI=1.05, 1.22 ≤0 mm Hg: HR=1.21, 95% CI=1.09, 1.34). A trend for increased MI risk was observed (>20 mm Hg: HR=1.0, referent 1 to 20 mm Hg: HR=1.09, 95% CI=0.93, 1.27 ≤0 mm Hg: HR=1.19, 95% CI=0.95, 1.50). Decreases in systolic blood pressure response per 1 SD were associated with an increased risk for all‐cause death (HR=1.08, 95% CI=1.05, 1.11) and incident MI (HR=1.09, 95% CI=1.03, 1.16).

Conclusions

Our results suggest that modest increases in exercise systolic blood pressure response are associated with adverse outcomes.

Introduction

Exercise stress testing is routinely used to identify individuals who potentially have obstructive coronary artery disease (CAD) and information regarding aerobic functional capacity also is obtained. 1 As a result of the increase in cardiac output that occurs with exercise, systolic arterial blood pressure is expected to rise 20 mm Hg per metabolic equivalent of task. 2 Reductions in systolic blood pressure during exercise stress testing are associated with left ventricular systolic dysfunction and the presence of severe obstructive CAD. 3 , 4

Several studies have shown that a decline in systolic blood pressure below resting value (eg, exercise‐induced hypotension) is associated with an increased risk of cardiovascular events. 5 , 6 , 7 Additionally, an increased risk of cardiovascular mortality has been observed with low maximal systolic blood pressure responses in men and in patients with known hypertension and peripheral arterial disease. 8 This led to the American Heart Association recommendation that decreases in systolic blood pressure >10 mm Hg below resting values are an absolute indication for exercise stress testing termination. 1 However, the aforementioned studies that led to this recommendation have been limited to specific subpopulations of predominately men.

Potentially, adverse outcomes are associated with even modest increases in exercise systolic blood pressure response, and this population merits closer evaluation for the presence of coronary heart disease. Such a finding would have important implications for populations that have not been extensively studied as data from diverse racial populations of men and women are lacking. Therefore, the purpose of this study was to examine the prognostic implications of decreased systolic blood pressure response during exercise treadmill stress testing using data from the Henry Ford ExercIse Testing (FIT) Project, a racially diverse registry of men and women aimed to elucidate the association between cardiorespiratory fitness and outcomes.

Methods

Study Population

Details of the design, procedures, and methods used in FIT have been previously described. 9 Briefly, the project population consists of 69 885 consecutive patients who underwent physician‐referred exercise treadmill stress testing in the Henry Ford Health System, including affiliated hospitals and ambulatory care centers throughout the metropolitan area of Detroit, Michigan between 1991 and 2009. Data regarding treadmill testing, medical history, and medications were collected by laboratory staff at the time of testing. Follow‐up data were collected from electronic medical records and administrative databases. The FIT Project was approved by the Henry Ford Health System institutional review board.

In this analysis, we examined the association between exercise systolic blood pressure response (peak systolic blood pressure—resting systolic blood pressure) and all‐cause death and incident myocardial infarction (MI). We excluded patients with missing baseline characteristics, medication data, and/or follow‐up data (n=1668). Additionally, participants with prior CAD (prior MI, coronary angioplasty, coronary artery bypass grafting surgery, or coronary angiography with evidence of obstructive CAD) (n=9946) and severe valve disease (n=423) were excluded. The focus of this analysis was largely on decreased systolic blood pressure response, and participants with exaggerated systolic blood pressure rise (male: peak systolic ≥210 mm Hg female: ≥190 mm Hg) were excluded (n=13 759). 1 , 10 The final sample included 44 089 (mean age 53±13 years, 45% female, 26% black) patients.

Exercise Stress Testing

Exercise treadmill stress testing was conducted using the Bruce protocol. 11 Patients <18 years old at the time of testing or those who underwent pharmacological stress testing, modified Bruce, and other non‐Bruce protocol tests were excluded from the database. Antihypertensive medications were held prior to stress testing. Resting heart rate was measured from the resting ECG and blood pressure was manually measured prior to each stress test with each participant in the seated position. Heart rate was measured continuously during testing and blood pressure values were measured every 3 minutes. Peak heart rate and blood pressure were the highest recorded values for each participant. Target heart rate was calculated as 85% of the age‐predicted maximal heart rate determined by the formula 220−age. Failure to achieve this heart rate was referred to as chronotropic incompetence. Initial treadmill speed was set at 2.7 km/h and increased to 4.0, 5.4, 6.7, 8.0, and 8.8 km/h on minutes 3, 6, 9, 12, and 15, respectively. Exercise workload was expressed in metabolic equivalents of task. We examined the association between exercise systolic blood pressure response as a categorical variable (>20 mm Hg: referent 1 to 20 mm Hg, and ≤0 mm Hg) and as a continuous variable per 1 SD decrease in the systolic blood pressure response. Exercise‐induced hypotension was defined as systolic blood pressure responses ≤0 mm Hg and values were grouped 1 to 20 mm Hg based on the graphical dose–response relationship between systolic blood pressure response and all‐cause death and MI using restricted cubic spline models with knots incorporated at the 5th, 50th, and 95th percentiles. 12

Patient Characteristics

Demographics, body mass index, prior history of cardiovascular disease, and smoking status were obtained at the time of treadmill testing. Diabetes mellitus was defined as a prior diagnosis of diabetes, the use of hypoglycemic medications including insulin, or a database‐verified diagnosis of diabetes. Hypertension was defined as a prior diagnosis of hypertension, use of antihypertensive medications, or a database‐verified diagnosis of hypertension. The blood pressure at the time of the test was not used to diagnose hypertension. Dyslipidemia was defined by prior diagnosis of any major lipid abnormality, the use of lipid‐lowering medications, or a database‐verified diagnosis of hypercholesterolemia or dyslipidemia.

All‐Cause Death

The National Death Index was used to obtain death dates for patients through April 2013. Linkage with the National Death Index was based on a multiple‐criteria deterministic matching algorithm, which included each patient's social security number, first name, last name, and date of birth. Complete matching occurred in >99.5% of patients in the FIT database.

Incident MI

We included incident fatal and nonfatal MI cases. Events were ascertained though linkage with administrative claim files from services delivered. These files included appropriate International Classification of Disease Codes. Complete follow‐up for MI events was available through May 2010.

Statistical Analysis

Categorical variables were reported as frequency and percentage, while continuous variables were reported as mean±SD. Statistical significance for categorical variables was tested using the χ 2 method and the Wilcoxon rank‐sum procedure for continuous variables. Follow‐up time was defined as the date of exercise stress testing until the outcome of interest, death, loss to follow‐up, or end of study period. Kaplan–Meier estimates were used to compute cumulative incidence curves for all‐cause death and incident MI by systolic blood pressure response, and the differences in estimates were compared using the log‐rank procedure. Cox regression was used to compute hazard ratios and 95% CI) for the association between systolic blood pressure response and all‐cause death and MI, separately. Multivariable models were constructed as follows: Model 1 adjusted for age, sex, and race Model 2 adjusted for Model 1 covariates plus smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, metabolic equivalents of task, and chronotropic incompetence. We tested for interactions between our main effect variable and age (stratified by median age), sex, and race (whites versus nonwhites) using Model 2. The proportional hazards assumption was not violated in our analysis. Statistical significance was defined as P<0.05 for the main effect model and tests for interaction. SAS ® version 9.3 (Cary, NC) was used for all analyses.

Results

Baseline characteristics stratified by systolic blood pressure response are shown in Figure 1. Differences in baseline characteristics across systolic blood pressure responses were observed for all characteristics with the exception of smoking (Table 1).

Table 1. Baseline Characteristics (N=44 089)

METs indicates metabolic equivalents of task.

a Statistical significance for categorical data tested using the χ 2 method and continuous data using the Wilcoxon rank‐sum procedure.

Figure 1. Cumulative incidence of all‐cause death by systolic blood pressure response. Cumulative incidence curves are statistically different (log‐rank P<0.0001).

Over a median follow‐up of 10 years (interquartile range=7.3, 13.8 years), a total of 4782 (11%) deaths occurred (incidence rate per 1000 person‐years=10.2, 95% CI=9.9, 10.5). The incidence rate (per 1000 person‐years) of all‐cause death increased with decreases in systolic blood pressure response (>20 mm Hg: 8.1, 95% CI=7.9, 8.4 1 to 20 mm Hg: 19.7, 95% CI=18.5, 20.9 ≤0 mm Hg: 33.8, 95% CI=30.8, 37.0). The cumulative incidence for all‐cause death by systolic blood pressure response is shown in Figure 1 (log‐rank P<0.0001).

Over a median follow‐up of 5.2 years (interquartile range=2.7, 8.1 years), a total of 1188 (2.7%) MIs occurred (incidence rate per 1000 person‐years=4.6, 95% CI 4.3, 4.8). The incidence rate (per 1000 person‐years) of MI increased with decreases in systolic blood pressure response (>20 mm Hg: 3.9, 95% CI=3.6, 4.1 1 to 20 mm Hg: 8.0, 95% CI=7.0, 9.1 ≤0 mm Hg: 12.5, 95% CI=10.2, 15.4). The cumulative incidence of MI by systolic blood pressure response is shown in Figure 2 (log‐rank P<0.0001).

Figure 2. Cumulative incidence of myocardial infarction by systolic blood pressure response. Cumulative incidence curves are statistically different (log‐rank P<0.0001).

An increased risk of all‐cause death was observed for participants with decreasing systolic blood pressure response (Table 2). Subgroup analyses are shown for blood pressure response as a continuous variable by age, sex, and race (Table 2). A differential association was observed when the analysis was stratified by age, with participants <52 years (median age) having a stronger association with all‐cause death compared with persons ≥52 years (Table 2).

Table 2. Risk of All‐Cause Death

HR indicates hazard ratio METs, metabolic equivalents of task.

a Adjusted for age, sex, and race.

b Adjusted for Model 1 covariates plus smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, METs, and chronotropic incompetence.

c Interactions tested using Model 2.

d All HRs presented are for the systolic blood pressure response per 1 SD decrease and were computed without the interaction term in the model.

e Dichotomized at the median age for study participants.

Although not significant, a trend was observed for increased MI risk when systolic blood pressure response was examined as a categorical variable (Table 3). However, an increased risk of MI was observed for the continuous variable per 1 SD decrease in systolic blood pressure response (Table 3). Subgroup analyses are shown in Table 3 for systolic blood pressure response as a continuous variable by age, sex, and race.

Table 3. Risk of Myocardial Infarction

HR indicates hazard ratio METs, metabolic equivalents of task.

a Adjusted for age, sex, and race.

b Adjusted for Model 1 covariates plus smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, METs, and chronotropic incompetence.

c Interactions tested using Model 2.

d Dichotomized at the median age for study participants.

e All HRs presented are for the systolic blood pressure response per 1 SD decrease and were computed without the interaction term in the model.

The graphical representations of the associations between systolic blood pressure response and risk of all‐cause death and MI are shown in Figures 3 and 4, respectively. As shown, the risk of all‐cause death and MI was observed to increase with decreasing systolic blood pressure responses. The risk was highest for those with responses lower than resting values.

Figure 3. Risk of all‐cause death across systolic blood pressure response. Each hazard ratio was computed with the median difference between peak and resting systolic blood pressure value of 42 mm Hg as the reference and was adjusted for age, sex, race, smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, MET s, and chronotropic incompetence. Dotted lines represent the 95% CI. MET indicates metabolic equivalent of task.

Figure 4. Risk of myocardial infarction across systolic blood pressure response. Each hazard ratio was computed with the median difference between peak and resting systolic blood pressure value of 42 mm Hg as the reference and was adjusted for age, sex, race, smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, MET s, and chronotropic incompetence. Dotted lines represent the 95% CI. MET indicates metabolic equivalent of task.

Discussion

In this analysis from the FIT Project, we have shown that an increased risk of adverse outcomes (eg, death and MI) exists in individuals who have lower systolic blood pressure responses during exercise stress testing, and the risk for these outcomes is highest among those with exercise‐induced hypotension. A differential association was observed between systolic blood pressure response and all‐cause death by age, with the association being stronger for younger compared with older patients.

Several studies have examined the association between decreased systolic blood pressure response during exercise stress testing and cardiovascular outcomes. An examination of 2036 patients referred to the Long Beach Veterans Medical Center showed that exercise‐induced hypotension in those with prior coronary heart disease is associated with an increased risk of cardiac events. 5 Similar results were observed in a prospective study of 588 males from the same Veterans Affairs Medical Center undergoing exercise stress testing. 6 Exercise‐induced hypotension also has been shown to predict long‐term mortality and major adverse cerebrovascular and cardiac events in patients referred for treadmill testing to evaluate for the presence of peripheral arterial disease. 7 Additionally, decreased exercise systolic blood pressure response (systolic blood pressure response ≤44 mm Hg) was shown to be associated with an increased risk of cardiovascular mortality. 8 In contrast, 2 studies of male patients from 2 university‐affiliated Veterans Affairs Medical Centers who underwent standard exercise treadmill testing failed to show an association with exercise‐induced hypotension and cardiovascular events when excluding patients with known cardiovascular disease. 13 , 14 The aforementioned studies largely focused on male populations with limited racial diversity, thus decreasing the generalizability to other populations. Our data confirm in a much larger cohort that decreases in exercise systolic blood pressure response, including exercise‐induced hypotension, are associated with an increased risk of all‐cause death and incident MI in both men and women from diverse racial backgrounds.

Several mechanisms have been proposed to explain the increased risk of adverse cardiovascular outcomes in those with decreased systolic blood pressure response during exercise stress testing. During exercise, systolic arterial blood pressure is expected to rise 20 mm Hg per metabolic equivalents of task as a result of increases in cardiac output. 2 However, when exercise systolic blood pressure decreases below resting values, this often signifies underlying cardiac pathology. Patients with exercise‐induced hypotension have been shown to have an increased risk of left ventricular systolic dysfunction and obstructive CAD, thus predisposing to a higher risk of cardiac events. 3 , 4 Abnormalities in the autonomic nervous system that occur during exercise stress testing are also possibly detected in persons with decreased systolic blood pressure responses. Autonomic imbalance has been linked to the development of heart failure, and similar disturbances possibly occur in those with decreased exercise systolic blood pressure response. 15 Although several explanations exist, further research is needed to determine the underlying mechanisms associated with the increased risk of adverse events in those with decreased systolic blood pressure response during exercise stress testing.

Currently, the American Heart Association recommends that persons with drops in systolic blood pressure >10 mm Hg below resting values terminate exercise stress testing. 1 These recommendations have been based on studies from male populations with limited generalizability to females and minority populations. 5 , 6 , 7 , 8 Our results suggest that the risk for adverse outcomes occurs with modest elevations in systolic blood pressure, and this risk is not limited to decreases in systolic blood pressure below resting values. Additionally, our results were similar between men and women and also between whites and nonwhites. In aggregate, our results suggest that even those with presumably “normal” exercise blood pressure responses (eg, increases by 1 to 20 mm Hg) merit closer evaluation for underlying coronary heart disease, and this suggestion is not limited to males or specific subpopulations. Therefore, a closer examination of current recommendations regarding exercise stress testing termination and exercise systolic blood pressure response is needed.

The current study should be interpreted in the context of several limitations. We examined the association between exercise systolic blood pressure response and all‐cause death and MI. All‐cause death was ascertained by linkage with the National Death Index, and we were unable to determine the specific cause of death for each patient. Additionally, incident MI was ascertained using data that were specific to the Henry Ford Health System, and any cases that occurred in other health systems possibly were missed. Furthermore, we included several covariates in our multivariable models that likely influenced mortality and the development of MI. However, we acknowledge that residual confounding remains a possibility.

In conclusion, using data from the FIT registry, we have shown that even modest elevations in systolic blood pressure during exercise stress testing are associated with an increased risk of all‐cause death and MI. Further research is needed to determine the pathophysiologic link between this abnormal response during exercise and the adverse outcomes examined. Potentially, this population merits closer evaluation for the presence of obstructive CAD.

Sources of Funding

WT Qureshi is funded by Ruth L. Kirschstein National Research Service Award Institutional Training Grant 5T32HL076132‐10.


Systolic Blood Pressure Response During Exercise Stress Testing: The Henry Ford ExercIse Testing (FIT) Project

The prognostic significance of modest elevations in exercise systolic blood pressure response has not been extensively examined.

Methods and Results

We examined the association between systolic blood pressure response and all‐cause death and incident myocardial infarction (MI) in 44 089 (mean age 53±13 years, 45% female, 26% black) patients who underwent exercise treadmill stress testing from the Henry Ford ExercIse Testing (FIT) Project (1991–2010). Exercise systolic blood pressure response was examined as a categorical variable (>20 mm Hg: referent 1 to 20 mm Hg, and ≤0 mm Hg) and per 1 SD decrease. Cox regression was used to compute hazard ratios (HR) and 95% CI for the association between systolic blood pressure response and all‐cause death and incident MI. Over a median follow‐up of 10 years, a total of 4782 (11%) deaths occurred and over 5.2 years, a total of 1188 (2.7%) MIs occurred. In a Cox regression analysis adjusted for demographics, physical fitness, and cardiovascular risk factors, an increased risk of death was observed with decreasing systolic blood pressure response (>20 mm Hg: HR=1.0, referent 1 to 20 mm Hg: HR=1.13, 95% CI=1.05, 1.22 ≤0 mm Hg: HR=1.21, 95% CI=1.09, 1.34). A trend for increased MI risk was observed (>20 mm Hg: HR=1.0, referent 1 to 20 mm Hg: HR=1.09, 95% CI=0.93, 1.27 ≤0 mm Hg: HR=1.19, 95% CI=0.95, 1.50). Decreases in systolic blood pressure response per 1 SD were associated with an increased risk for all‐cause death (HR=1.08, 95% CI=1.05, 1.11) and incident MI (HR=1.09, 95% CI=1.03, 1.16).

Conclusions

Our results suggest that modest increases in exercise systolic blood pressure response are associated with adverse outcomes.

Introduction

Exercise stress testing is routinely used to identify individuals who potentially have obstructive coronary artery disease (CAD) and information regarding aerobic functional capacity also is obtained. 1 As a result of the increase in cardiac output that occurs with exercise, systolic arterial blood pressure is expected to rise 20 mm Hg per metabolic equivalent of task. 2 Reductions in systolic blood pressure during exercise stress testing are associated with left ventricular systolic dysfunction and the presence of severe obstructive CAD. 3 , 4

Several studies have shown that a decline in systolic blood pressure below resting value (eg, exercise‐induced hypotension) is associated with an increased risk of cardiovascular events. 5 , 6 , 7 Additionally, an increased risk of cardiovascular mortality has been observed with low maximal systolic blood pressure responses in men and in patients with known hypertension and peripheral arterial disease. 8 This led to the American Heart Association recommendation that decreases in systolic blood pressure >10 mm Hg below resting values are an absolute indication for exercise stress testing termination. 1 However, the aforementioned studies that led to this recommendation have been limited to specific subpopulations of predominately men.

Potentially, adverse outcomes are associated with even modest increases in exercise systolic blood pressure response, and this population merits closer evaluation for the presence of coronary heart disease. Such a finding would have important implications for populations that have not been extensively studied as data from diverse racial populations of men and women are lacking. Therefore, the purpose of this study was to examine the prognostic implications of decreased systolic blood pressure response during exercise treadmill stress testing using data from the Henry Ford ExercIse Testing (FIT) Project, a racially diverse registry of men and women aimed to elucidate the association between cardiorespiratory fitness and outcomes.

Methods

Study Population

Details of the design, procedures, and methods used in FIT have been previously described. 9 Briefly, the project population consists of 69 885 consecutive patients who underwent physician‐referred exercise treadmill stress testing in the Henry Ford Health System, including affiliated hospitals and ambulatory care centers throughout the metropolitan area of Detroit, Michigan between 1991 and 2009. Data regarding treadmill testing, medical history, and medications were collected by laboratory staff at the time of testing. Follow‐up data were collected from electronic medical records and administrative databases. The FIT Project was approved by the Henry Ford Health System institutional review board.

In this analysis, we examined the association between exercise systolic blood pressure response (peak systolic blood pressure—resting systolic blood pressure) and all‐cause death and incident myocardial infarction (MI). We excluded patients with missing baseline characteristics, medication data, and/or follow‐up data (n=1668). Additionally, participants with prior CAD (prior MI, coronary angioplasty, coronary artery bypass grafting surgery, or coronary angiography with evidence of obstructive CAD) (n=9946) and severe valve disease (n=423) were excluded. The focus of this analysis was largely on decreased systolic blood pressure response, and participants with exaggerated systolic blood pressure rise (male: peak systolic ≥210 mm Hg female: ≥190 mm Hg) were excluded (n=13 759). 1 , 10 The final sample included 44 089 (mean age 53±13 years, 45% female, 26% black) patients.

Exercise Stress Testing

Exercise treadmill stress testing was conducted using the Bruce protocol. 11 Patients <18 years old at the time of testing or those who underwent pharmacological stress testing, modified Bruce, and other non‐Bruce protocol tests were excluded from the database. Antihypertensive medications were held prior to stress testing. Resting heart rate was measured from the resting ECG and blood pressure was manually measured prior to each stress test with each participant in the seated position. Heart rate was measured continuously during testing and blood pressure values were measured every 3 minutes. Peak heart rate and blood pressure were the highest recorded values for each participant. Target heart rate was calculated as 85% of the age‐predicted maximal heart rate determined by the formula 220−age. Failure to achieve this heart rate was referred to as chronotropic incompetence. Initial treadmill speed was set at 2.7 km/h and increased to 4.0, 5.4, 6.7, 8.0, and 8.8 km/h on minutes 3, 6, 9, 12, and 15, respectively. Exercise workload was expressed in metabolic equivalents of task. We examined the association between exercise systolic blood pressure response as a categorical variable (>20 mm Hg: referent 1 to 20 mm Hg, and ≤0 mm Hg) and as a continuous variable per 1 SD decrease in the systolic blood pressure response. Exercise‐induced hypotension was defined as systolic blood pressure responses ≤0 mm Hg and values were grouped 1 to 20 mm Hg based on the graphical dose–response relationship between systolic blood pressure response and all‐cause death and MI using restricted cubic spline models with knots incorporated at the 5th, 50th, and 95th percentiles. 12

Patient Characteristics

Demographics, body mass index, prior history of cardiovascular disease, and smoking status were obtained at the time of treadmill testing. Diabetes mellitus was defined as a prior diagnosis of diabetes, the use of hypoglycemic medications including insulin, or a database‐verified diagnosis of diabetes. Hypertension was defined as a prior diagnosis of hypertension, use of antihypertensive medications, or a database‐verified diagnosis of hypertension. The blood pressure at the time of the test was not used to diagnose hypertension. Dyslipidemia was defined by prior diagnosis of any major lipid abnormality, the use of lipid‐lowering medications, or a database‐verified diagnosis of hypercholesterolemia or dyslipidemia.

All‐Cause Death

The National Death Index was used to obtain death dates for patients through April 2013. Linkage with the National Death Index was based on a multiple‐criteria deterministic matching algorithm, which included each patient's social security number, first name, last name, and date of birth. Complete matching occurred in >99.5% of patients in the FIT database.

Incident MI

We included incident fatal and nonfatal MI cases. Events were ascertained though linkage with administrative claim files from services delivered. These files included appropriate International Classification of Disease Codes. Complete follow‐up for MI events was available through May 2010.

Statistical Analysis

Categorical variables were reported as frequency and percentage, while continuous variables were reported as mean±SD. Statistical significance for categorical variables was tested using the χ 2 method and the Wilcoxon rank‐sum procedure for continuous variables. Follow‐up time was defined as the date of exercise stress testing until the outcome of interest, death, loss to follow‐up, or end of study period. Kaplan–Meier estimates were used to compute cumulative incidence curves for all‐cause death and incident MI by systolic blood pressure response, and the differences in estimates were compared using the log‐rank procedure. Cox regression was used to compute hazard ratios and 95% CI) for the association between systolic blood pressure response and all‐cause death and MI, separately. Multivariable models were constructed as follows: Model 1 adjusted for age, sex, and race Model 2 adjusted for Model 1 covariates plus smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, metabolic equivalents of task, and chronotropic incompetence. We tested for interactions between our main effect variable and age (stratified by median age), sex, and race (whites versus nonwhites) using Model 2. The proportional hazards assumption was not violated in our analysis. Statistical significance was defined as P<0.05 for the main effect model and tests for interaction. SAS ® version 9.3 (Cary, NC) was used for all analyses.

Results

Baseline characteristics stratified by systolic blood pressure response are shown in Figure 1. Differences in baseline characteristics across systolic blood pressure responses were observed for all characteristics with the exception of smoking (Table 1).

Table 1. Baseline Characteristics (N=44 089)

METs indicates metabolic equivalents of task.

a Statistical significance for categorical data tested using the χ 2 method and continuous data using the Wilcoxon rank‐sum procedure.

Figure 1. Cumulative incidence of all‐cause death by systolic blood pressure response. Cumulative incidence curves are statistically different (log‐rank P<0.0001).

Over a median follow‐up of 10 years (interquartile range=7.3, 13.8 years), a total of 4782 (11%) deaths occurred (incidence rate per 1000 person‐years=10.2, 95% CI=9.9, 10.5). The incidence rate (per 1000 person‐years) of all‐cause death increased with decreases in systolic blood pressure response (>20 mm Hg: 8.1, 95% CI=7.9, 8.4 1 to 20 mm Hg: 19.7, 95% CI=18.5, 20.9 ≤0 mm Hg: 33.8, 95% CI=30.8, 37.0). The cumulative incidence for all‐cause death by systolic blood pressure response is shown in Figure 1 (log‐rank P<0.0001).

Over a median follow‐up of 5.2 years (interquartile range=2.7, 8.1 years), a total of 1188 (2.7%) MIs occurred (incidence rate per 1000 person‐years=4.6, 95% CI 4.3, 4.8). The incidence rate (per 1000 person‐years) of MI increased with decreases in systolic blood pressure response (>20 mm Hg: 3.9, 95% CI=3.6, 4.1 1 to 20 mm Hg: 8.0, 95% CI=7.0, 9.1 ≤0 mm Hg: 12.5, 95% CI=10.2, 15.4). The cumulative incidence of MI by systolic blood pressure response is shown in Figure 2 (log‐rank P<0.0001).

Figure 2. Cumulative incidence of myocardial infarction by systolic blood pressure response. Cumulative incidence curves are statistically different (log‐rank P<0.0001).

An increased risk of all‐cause death was observed for participants with decreasing systolic blood pressure response (Table 2). Subgroup analyses are shown for blood pressure response as a continuous variable by age, sex, and race (Table 2). A differential association was observed when the analysis was stratified by age, with participants <52 years (median age) having a stronger association with all‐cause death compared with persons ≥52 years (Table 2).

Table 2. Risk of All‐Cause Death

HR indicates hazard ratio METs, metabolic equivalents of task.

a Adjusted for age, sex, and race.

b Adjusted for Model 1 covariates plus smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, METs, and chronotropic incompetence.

c Interactions tested using Model 2.

d All HRs presented are for the systolic blood pressure response per 1 SD decrease and were computed without the interaction term in the model.

e Dichotomized at the median age for study participants.

Although not significant, a trend was observed for increased MI risk when systolic blood pressure response was examined as a categorical variable (Table 3). However, an increased risk of MI was observed for the continuous variable per 1 SD decrease in systolic blood pressure response (Table 3). Subgroup analyses are shown in Table 3 for systolic blood pressure response as a continuous variable by age, sex, and race.

Table 3. Risk of Myocardial Infarction

HR indicates hazard ratio METs, metabolic equivalents of task.

a Adjusted for age, sex, and race.

b Adjusted for Model 1 covariates plus smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, METs, and chronotropic incompetence.

c Interactions tested using Model 2.

d Dichotomized at the median age for study participants.

e All HRs presented are for the systolic blood pressure response per 1 SD decrease and were computed without the interaction term in the model.

The graphical representations of the associations between systolic blood pressure response and risk of all‐cause death and MI are shown in Figures 3 and 4, respectively. As shown, the risk of all‐cause death and MI was observed to increase with decreasing systolic blood pressure responses. The risk was highest for those with responses lower than resting values.

Figure 3. Risk of all‐cause death across systolic blood pressure response. Each hazard ratio was computed with the median difference between peak and resting systolic blood pressure value of 42 mm Hg as the reference and was adjusted for age, sex, race, smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, MET s, and chronotropic incompetence. Dotted lines represent the 95% CI. MET indicates metabolic equivalent of task.

Figure 4. Risk of myocardial infarction across systolic blood pressure response. Each hazard ratio was computed with the median difference between peak and resting systolic blood pressure value of 42 mm Hg as the reference and was adjusted for age, sex, race, smoking, hypertension, diabetes, obesity, hyperlipidemia, antihypertensive medication use, lipid‐lowering medication use, aspirin, MET s, and chronotropic incompetence. Dotted lines represent the 95% CI. MET indicates metabolic equivalent of task.

Discussion

In this analysis from the FIT Project, we have shown that an increased risk of adverse outcomes (eg, death and MI) exists in individuals who have lower systolic blood pressure responses during exercise stress testing, and the risk for these outcomes is highest among those with exercise‐induced hypotension. A differential association was observed between systolic blood pressure response and all‐cause death by age, with the association being stronger for younger compared with older patients.

Several studies have examined the association between decreased systolic blood pressure response during exercise stress testing and cardiovascular outcomes. An examination of 2036 patients referred to the Long Beach Veterans Medical Center showed that exercise‐induced hypotension in those with prior coronary heart disease is associated with an increased risk of cardiac events. 5 Similar results were observed in a prospective study of 588 males from the same Veterans Affairs Medical Center undergoing exercise stress testing. 6 Exercise‐induced hypotension also has been shown to predict long‐term mortality and major adverse cerebrovascular and cardiac events in patients referred for treadmill testing to evaluate for the presence of peripheral arterial disease. 7 Additionally, decreased exercise systolic blood pressure response (systolic blood pressure response ≤44 mm Hg) was shown to be associated with an increased risk of cardiovascular mortality. 8 In contrast, 2 studies of male patients from 2 university‐affiliated Veterans Affairs Medical Centers who underwent standard exercise treadmill testing failed to show an association with exercise‐induced hypotension and cardiovascular events when excluding patients with known cardiovascular disease. 13 , 14 The aforementioned studies largely focused on male populations with limited racial diversity, thus decreasing the generalizability to other populations. Our data confirm in a much larger cohort that decreases in exercise systolic blood pressure response, including exercise‐induced hypotension, are associated with an increased risk of all‐cause death and incident MI in both men and women from diverse racial backgrounds.

Several mechanisms have been proposed to explain the increased risk of adverse cardiovascular outcomes in those with decreased systolic blood pressure response during exercise stress testing. During exercise, systolic arterial blood pressure is expected to rise 20 mm Hg per metabolic equivalents of task as a result of increases in cardiac output. 2 However, when exercise systolic blood pressure decreases below resting values, this often signifies underlying cardiac pathology. Patients with exercise‐induced hypotension have been shown to have an increased risk of left ventricular systolic dysfunction and obstructive CAD, thus predisposing to a higher risk of cardiac events. 3 , 4 Abnormalities in the autonomic nervous system that occur during exercise stress testing are also possibly detected in persons with decreased systolic blood pressure responses. Autonomic imbalance has been linked to the development of heart failure, and similar disturbances possibly occur in those with decreased exercise systolic blood pressure response. 15 Although several explanations exist, further research is needed to determine the underlying mechanisms associated with the increased risk of adverse events in those with decreased systolic blood pressure response during exercise stress testing.

Currently, the American Heart Association recommends that persons with drops in systolic blood pressure >10 mm Hg below resting values terminate exercise stress testing. 1 These recommendations have been based on studies from male populations with limited generalizability to females and minority populations. 5 , 6 , 7 , 8 Our results suggest that the risk for adverse outcomes occurs with modest elevations in systolic blood pressure, and this risk is not limited to decreases in systolic blood pressure below resting values. Additionally, our results were similar between men and women and also between whites and nonwhites. In aggregate, our results suggest that even those with presumably “normal” exercise blood pressure responses (eg, increases by 1 to 20 mm Hg) merit closer evaluation for underlying coronary heart disease, and this suggestion is not limited to males or specific subpopulations. Therefore, a closer examination of current recommendations regarding exercise stress testing termination and exercise systolic blood pressure response is needed.

The current study should be interpreted in the context of several limitations. We examined the association between exercise systolic blood pressure response and all‐cause death and MI. All‐cause death was ascertained by linkage with the National Death Index, and we were unable to determine the specific cause of death for each patient. Additionally, incident MI was ascertained using data that were specific to the Henry Ford Health System, and any cases that occurred in other health systems possibly were missed. Furthermore, we included several covariates in our multivariable models that likely influenced mortality and the development of MI. However, we acknowledge that residual confounding remains a possibility.

In conclusion, using data from the FIT registry, we have shown that even modest elevations in systolic blood pressure during exercise stress testing are associated with an increased risk of all‐cause death and MI. Further research is needed to determine the pathophysiologic link between this abnormal response during exercise and the adverse outcomes examined. Potentially, this population merits closer evaluation for the presence of obstructive CAD.

Sources of Funding

WT Qureshi is funded by Ruth L. Kirschstein National Research Service Award Institutional Training Grant 5T32HL076132‐10.


Blood Pressure Control By Baroreceptors

The mean arterial pressure (MAP), also considered as the perfusion pressure, is taken as the pressure difference between the arteries and the veins. The regulation of blood pressure is done in order to maintain the MAP.

The MAP dictates the amount of oxygen and nutrients that is supplied by the blood vessels and the waste that is carried away from the tissues.

Regulation Of Blood Pressure

The body has the ability to counteract long term as well as short term changes in blood pressure. The long term pressure changes cause the body to respond through the activation of renin-angiotensin system.

Rapid/short term changes in blood pressure compel the body to activate the following receptors:

  • Baroreceptors are present on the arch of aorta and carotid sinus
  • Chemoreceptors are present in the carotid sinuses, arch of aorta and medulla oblongata
  • Atrial receptors are present on the wall of right atrium

Baroreceptors

The baroreceptors are the pressure sensing bodies. They are also called stretch receptors.They are modified nerve endings attached to the cytoskeleton present within the nerve endings. The receptors are sensitive to rapid offsets in blood pressure. The baroreceptors are densely situated on the walls of the arch of aorta and the carotid sinus. The carotid sinus is present on the base of internal carotid artery at the level of bifurcation of the common carotid artery. The sinus area is slightly dilated as the tunica media which is normally comprised of muscles, is relatively thin. The tunica adventitia, on the other hand, is thicker than usual. This is the layer of the blood vessels where the nerve receptors are situated. Same is true for the location of baroreceptors on the arch of aorta.

Rapid offsets in pressure can occur, for example, in a previously standing person who suddenly sits down. During the process, a large volume of blood is shifted from the peripheral to the central regions of the body. Consequently, a large volume of blood enters the heart and this volume overload or increased preload causes the heart to increase its cardiac output. A simultaneous increase in blood pressure will also be observed with increase in cardiac output. The increase in blood pressure is registered by the baroreceptors.

Similarly, a drop in blood pressure is registered by the baroreceptors when the person stands up suddenly from a sitting position. High blood pressure in the blood vessels causes stretch of these receptors which results in movement of sodium ions into the nerve endings, thereby, initiating an action potential.

These baroreceptors have a baseline firing pattern. That means they have an intrinsic potential to generate action potentials at a particular frequency at all times. This frequency is increased when the baroreceptors receive a stretch stimulus secondary to increase in blood pressure. The carotid sinuses increase their rate of impulse generation when the pressure in them builds up to values greater than 50 mm Hg. Below this threshold pressure, the carotid baroreceptors fail to initiate an action potential. On the other hand, the arch of aorta can record drops in blood pressure up to 30 mm Hg. The upper limit for blood pressure, after which the frequency of action potential stops increasing, is 175 mm Hg. The normal MAP is calculated to be 93 mm Hg. At this pressure, the baroreceptors are believed to be the most sensitive and even slight changes in pressure will result in rapid firing of action potentials.

At blood pressures lower than 30 mm Hg, the chemoreceptors come into play. The chemoreceptors function by sensing the arterial concentration of carbon dioxide, oxygen, Ph and other metabolites . They do not detect changes in blood pressure.

Baroreceptor Reflex

The baroreceptor reflex like other reflex arcs is comprised of three units:

  • Afferent nerve carrying impulses from the receptors
  • Central processing unit
  • An efferent nerve that innervates the effector

Afferent impulses from the carotid sinus are carried by the Herring nerve, a branch of Glossopharyngeal nerve (CN-9). In the case of baroreceptors present on the arch of aorta, the Vagus nerve (CN-10) is the afferent nerve that carries impulses to the spinal cord. Both, the Vagus nerve and the Glossopharyngeal nerve, feed impulses from the baroreceptors into the nucleus of tractus solitarius. These nuclei are situated in the medulla of the spinal cord and their job is to process the incoming afferent impulses. Also within the Medulla and lower 1/3rd of the Pons, there are vasoconstricting center, the vasodilatory center and the cardio-inhibitory center. These centers receive processed impulses from the nucleus of tractus solitarius and from here efferent impulses in the form of sympathetic and parasympathetic nerves arise. Impulses are carried to the heart via the parasympathetic Vagus nerve. Sympathetic impulses travel down the intermedio-lateral segment of the spinal cord and give rise to efferent motor spinal nerves which enter the sympathetic ganglion running parallel to the spinal cord. Postganglionic sympathetic nerves ultimately supply the heart and the peripheral vasculature. Another preganglionic sympathetic nerve also supplies the adrenal medulla which results in the release of epinephrine and norepinephrine, which further contribute in enhancing the sympathetic activity. The end result is either an increase or decrease in the blood pressure, thereby correcting the disturbance in hemodynamics of the body. This phenomenon is also referred to as the buffering effect, since the change in pressure is buffered back to normal. The Vagus and Glossopharyngeal nerves, because of the same reason, are therefore known as the buffering nerves.

Factors Responsible For Change in Mean Arterial Pressure

MAP = Heart Rate x Cardiac Output

Whereas, CO = SV (stroke volume) x TPR (total peripheral resistance)

Therefore, MAP = HR x SV x TPR

The stroke volume is altered by altering the force of contractility of the heart muscles. The sympathetic nerves supplying the heart muscles affect the stroke volume. The parasympathetic nerves supplying the SA and AV node are responsible for producing changes in heart rate. The TPR can be increased or decreased by changing the diameter of peripheral vasculature which is under the control of the sympathetic nervous system.

Effects of Baroreceptors in Various Conditions

Due To Changes In Blood Pressure

  • Reduced Blood Pressure: Reduction in blood pressure will result in a decrease in the number of afferent impulses from the baroreceptors. The sympathetic activity will increase and as a result, the TPR, HR and the stroke volume will all increase. At the same time, the parasympathetic input will taper down. All these changes will result in increasing the blood pressure back to normal.
  • Increased Blood Pressure: This happens in situations like exercise or stress. Increased blood pressure will result in stretching of the stretch receptors. This increases the frequency of afferent impulses. Sympathetic supply will decrease and the parasympathetic system will take over. Finally, the blood pressure is decreased back to normal.

Due To Changes In Cardiac Output

  • Decreased Cardiac Output: Occurs in situations of vomiting, diarrhea, hemorrhage etc. As a result of these, both the volume, and therefore pressure of the blood decreases. Afferent impulse firing of the baroreceptors decreases. As a consequence, there’s a sympathetic overflow which causes an increase in HR, TPR and SV. Due to an increase in these parameters, the blood pressure is raised back to normal.
  • Increased Cardiac Output: There’s an increased impulse generation from the baroreceptors due stretch caused by increased volume of blood. This increased afferent input from the baroreceptors results in activation of the PANS. Once activated, the parasympathetic nervous system decreases the blood pressure back to normal.

Massaging The Carotid Sinus

Massaging the carotid sinuses physically increases the pressure on the baroreceptors present there. The carotid baroreceptors respond by increasing the rate of afferent impulse firing. The sympathetic system will be shut down and the parasympathetic system is activated. This results in decrease in blood pressure of the body.

Carotid massage by activating parasympathetic nervous system increases AV nodal refractory period, thereby decreasing AV node conduction and finally decreasing Heart Rate. This is the reason Carotid sinus massage is the initial menuever used in the treatment of paroxysmal supra-ventricular tachycardia.

Stenosis Of The Carotids

Stenosis of carotids proximal to the sinus or obstruction of the carotids due to atherosclerosis will cause the baroreceptors to register a decrease in pressure. Therefore, sympathetic system activation follows. Increased sympathetic activity causes a resultant increase in blood pressure. This increase in blood pressure may cause hypertension in an otherwise normal person.

Baroreceptor responses are summarized in the table below

It’s important to understand that control of BP by baroreceptor is a short term regulation of blood pressure. Any short term derangements are dealt via the baroreceptor response, whereas long term control of the BP is controlled via the RAAS (Renin Angiotensin Aldosterone System).

The baroreceptors also have the ability to adapt to chronic changes in blood pressure. If the mean pressure is changed over time to a new value, the baroreceptors will start using that MAP as the baseline. Any subsequent blood pressure changes will then be rectified keeping in view the new baseline value of MAP.

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Written by Mobeen Syed
October 19, 2016 . Leave a Comment


INTRODUCTION

Alcohol (ethyl alcohol or ethanol, C2H5OH) from fermented grain, fruit juice and honey have been used for thousands of years. Fermented beverages existed and alcoholic drinks used in early Egyptian civilization, in China around 7000 BC, in India, between 3000 and 2000 BC, in Babylon as early as 2700 BC, in Greece, and in South America[1]. In the sixteenth century, alcohol (called “spirits”) was used largely for medicinal purposes[2]. At the beginning and mid of the eighteenth century, spirits was used heavily in Britain. The nineteenth century brought a change in attitudes and the temperance movement began promoting the moderate use of alcohol. In 1920 the United States passed a law prohibiting the manufacture, sale, import and export of intoxicating liquors. Current research suggests that the moderate consumption of alcohol is beneficial to the cardiovascular system and lowers the blood pressure[3-5]. A preclinical study also showed a decrease in systolic blood pressure in rats fed ethanol (1.0 g/kg) for 12 wk[6]. Moderate drinking is generally considered to be: Two drinks a day for men younger than age 65, one drink a day for men age 65 and older and one drink a day for women of any age. A drink is 12 ounces (355 milliliters) of beer, 5 ounces (148 milliliters) of wine or 1.5 ounces (44 milliliters) of 80-proof distilled spirits. Low to moderate drinking has been shown to reduce the incidence of coronary heart disease[3-5] and to increase longevity. It has clearly been a major analgesic, and one widely available to people in pain[1,2,7].

Today, alcoholic beverages are consumed regularly by most of the human societies in the world. However its abuse is a major public health problem in the world. In United States alcohol abuse affects more than 20 million individuals leading to loss of 100000 lives annually[8,9].Chronic high dose ethanol consumption most commonly causes hepatic, gastrointestinal, nervous and cardiovascular injuries leading to physiological dysfunctions[10]. A cause and effect relationship between regular alcohol consumption and blood pressure elevation (hypertension) was first suggested in 1915 by Lian et al[11]. Recent epidemiological and clinical studies have demonstrated that chronic ethanol consumption (more than three drinks per day, 30 g ethanol) is associated with an increased incidence of hypertension and an increased risk of cardiovascular diseases[12-17]. The magnitude of the increase in blood pressure in heavy drinkers averages about 5 to 10 mmHg, with systolic increases nearly always greater than diastolic increases[18]. Similar changes in blood pressure were also reported in preclinical studies[19-22]. In the Framingham cohort[23,24], there was an increase of 7 mmHg in mean arterial pressure when heavy alcohol users were compared with all others. In some epidemiological studies a linear dose-response relationship has been established, sometimes starting with a consumption threshold of 3 drinks per day (30 g of ethanol)[25-33]. In others, the relationship has been nonlinear, especially in women, and some authors have speculated that ingestion of smaller quantities of alcohol may reduce blood pressure[34-38]. Only a few studies have addressed the relationship between alcohol and hypertension in the elderly, and most of them have shown a strong association between hypertension prevalence and alcohol intake[39,40]. However preclinical studies have also shown a linear relationship between blood pressure and ingestion of alcohol[6]. The molecular mechanisms and possible mediators through which alcohol causes vascular injury and raises blood pressure remain elusive. This review focuses the mechanisms implicated with alcohol-induced hypertension and the strategies to control, prevent or to treat alcohol-induced elevation of blood pressure.


Abstract

The rise in blood pressure with age is a major risk factor for cardiovascular and renal disease, stroke, and type 2 diabetes mellitus. Age-related increases in blood pressure have been observed in almost every population, except among hunter-gatherers, farmers, and pastoralists. Here we tested for age-related increases in blood pressure among Tsimane forager-farmers. We also test whether lifestyle changes associated with modernization lead to higher blood pressure and a greater rate of age-related increase in blood pressure. We measured blood pressure longitudinally on 2248 adults age ≥20 years (n=6468 observations over 8 years). Prevalence of hypertension was 3.9% for women and 5.2% for men, although diagnosis of persistent hypertension based on multiple observations reduced prevalence to 2.9% for both sexes. Mixed-effects models revealed systolic, diastolic, and pulse blood pressure increases of 2.86 (P<0.001), 0.95 (P<0.001), and 1.95 mmHg (P<0.001) per decade for women and 0.91 (P<0.001), 0.93 (P<0.001), and −0.02 mmHg (P=0.93) for men, substantially lower than rates found elsewhere. Lifestyle factors, such as smoking and Spanish fluency, had minimal effect on mean blood pressure and no effect on age-related increases in blood pressure. Greater town proximity was associated with a lower age-related increase in pulse pressure. Effects of modernization were, therefore, deemed minimal among Tsimane, in light of their lean physique, active lifestyle, and protective diet.

Introduction

See Editorial Commentary, pp 6–7

An age-related increase in blood pressure (BP) is viewed as a universal feature of human aging. 1–3 Among Westerners over age 40 years, systolic BP (SBP) increases by ≈7 mmHg per decade. 4 Epidemiological surveys show a progressive increase in SBP with age, reaching an average of ≈140 mmHg by the eighth decade. 5 Diastolic BP (DBP) also increases with age but at a lower rate than SBP DBP may even fall at late ages. 6 Women show lower SBP and DBP than men up until the age of menopause, when women's SBP surpasses that of men. 7 By age 70 years, more than three quarters of US adults have hypertension.

Understanding the conditions affecting age-related BP increase is of obvious clinical importance. Higher BP is associated with cardiovascular and renal disease across diverse populations, even controlling for other factors. 5 Hypertension is the leading cause of cardiovascular mortality, and age-related BP increase is a high-priority target for intervention. 8

The only reported cases of no age-related BP increase come from studies of subsistence-level populations. 9–11 These studies, however, are problematic: they are cross-sectional use small, sometimes biased samples and often do not specify explicit measurement methods. Age estimates of older adults are also poor. 12 Because of epidemiological and economic transitions, cohort effects may also have muted age effects younger adults may have higher BP than older adults did when they were younger.

Nonetheless, results from many studies suggest that “modernization” results in changes in diet, adiposity, activity, and psychosocial stress, leading to higher BP and greater age-related increases in BP. 13–15 Although available evidence shows that hypertension is more common among those with modern lifestyles, it is unclear whether these changes impact the rate of increase in BP. It is also unclear whether these changes impact everyone equally or just high risk subpopulations. Heterogeneity in susceptibility and modernization could reveal further variability in longitudinal age trajectories of BP.

Here we assess the extent to which BP increases with age using longitudinal and cross-sectional data collected among Tsimane of the Bolivian Amazon. Tsimane are lowland forager-horticulturalists (population, ≈11000) subsisting on plantains, rice, corn and manioc, fish, and hunted game. Tsimane are currently undergoing epidemiological and technological transitions, 16 although there was no electricity, running water, or waste management at the time of study. Villages vary in their degree of healthcare access. Modernization takes several forms, including visits to the town of San Borja (population, ≈24000), wage labor with loggers or colonists, debt peonage with itinerant river merchants, and schooling. Schools now exist in >75% of villages, but many older adults have little or no schooling.

We first assessed hypertension prevalence and examined age-related changes in SBP, DBP, and pulse pressure (PP) to test the general hypothesis that BP increase is a robust feature of human aging. We then tested whether both BP and age-related increase in BP increased with modernization, operationalized by Spanish fluency, distance to town, smoking frequency, and body mass index (BMI). We also assessed whether an increase in BP with age occurred uniformly or was instead concentrated among a high-risk subpopulation.

Methods

Study Population

A total of 2248 adults aged 20 to 90 years (n=82 villages) participated in the Tsimane Health and Life History Project from July 2002 to December 2010. Adults were sampled anywhere from 1 to 9 times during medical rounds, yielding a sample of 6468 person-observations 61% of adults were sampled at least twice and 36% ≥4 times (Table S1, available in the online-only Data Supplement). Sample size varied from 268 to 1186 individuals across 9 medical rounds (Table S2).

BP and Controls

SBP and DBP were measured on the right arm by trained Bolivian physicians with a Welch Allyn Tycos Aneroid 5090 sphygmomanometer and Littman stethoscope. Patients were seated or supine for ≥20 minutes before measurements. After 2008, all of the hypertensive readings were repeated after ≥30 minutes to confirm preliminary diagnoses. No Tsimane has ever taken medication to control hypertension. We use the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure classification scheme to define BP categories as hypertensive (SBP ≥140 mmHg or DBP ≥90 mmHg), prehypertensive (120–139 mmHg SBP or 80–89 mmHg DBP), and normotensive (SBP <120 mmHg and DBP <80 mmHg).

Height (in centimeters) was measured by trained Tsimane research assistants with a portable Seca stadiometer. Weight (in kilograms) and body fat percentage were measured using a Tanita BF-572 weigh scale.

Modernization

Village-level variance in distance to San Borja is substantial (mean±SD, 41±23 km minimum, 6 maximum, 82). Highest level of schooling and Spanish fluency were assessed during census updates and demographic interviews. Cumulative smoking was measured in cigarette pack-years based on interviews of number of cigarettes smoked per week and age at which the interviewee started smoking. One pack-year is equal to a pack of cigarettes smoked per day for 1 year. Given potential problems with recall bias, cumulative smoking experience was categorized into tertiles, including first (0.003–0.070 pack-years), second (0.07–0.30 pack-years), or third (>0.30 pack-years).

Statistical Analysis

Cross-Sectional Analyses

We used mixed- and fixed-effect models with linear and nonlinear age parameters. Linear models were fit with the lm and lme procedures in R 2.13.1. Nonlinear models used generalized additive models. 17,18 Generalized additive models use a thin-point spline to fit nonlinear age patterns while allowing for the simultaneous inclusion of parametric terms. Generalized additive models were fit with gam in the mgcv package and gamm4 in the gamm4 package. Mixed models were used to control for both individual variation in age trajectories and correlated errors between repeated samples. 19

Longitudinal Rates of BP Change

Longitudinal analyses included only individuals with ≥5 years between first and last observation (please see the online-only Data Supplement). Repeat BP values were recoded as changes from the mean of a subject's BP measures (ΔBP) times were coded as days before or after the subject's median examination date. Linear models were fit to ΔBP including subject identification, a subject-by-time interaction term, season, and pregnancy status as controls. Parameter values for ΔBP were obtained from the subject-by-time interaction terms.

Two-Stage Mixed Model

To examine the effect of modernization on absolute BP levels and rates of BP change, we use a 2-stage mixed model (Tables 2 and S3). In the first stage, a standard mixed generalized additive model was run with a nonparametric age term, and individual variation in slope was modeled as a random effect. Individual slopes were obtained by adding the overall population slope for an individual's age plus that individual's random slope, both from the stage 1 model. These slopes were used as the dependent variable in model 2 to examine factors affecting rate of BP change.

Ethical Concerns

Informed consent was obtained for all of the protocols at 3 levels, Tsimane government, community, and individual. After explanation of protocols by bilingual Spanish-Tsimane research assistants, consent forms were either signed by literate participants or fingerprinted by nonliterate participants. All of the protocols have been approved by the institutional review boards at University of New Mexico and University of California-Santa Barbara.

Results

Sample Characteristics

Average age was 38.0 and 39.3 years for women and men, respectively (Table 1). Women represented 52.6% of observations. In comparison with normotensives, hypertensive men and women were older, shorter, had more body fat, were less likely to be nonsmokers, were less educated, and were more likely to speak Spanish.

Table 1. Sample Means by BP Status for Tsimane Adults Aged ≥20 y

For each individual the median value of repeated measures on a given variable was used to calculate group means and determine hypertensive category. NvP indicates normal vs prehypertensive NvH, normal vs hypertensive PvH prehypertensive vs hypertensive NS, not significant SBP, systolic blood pressure DBP, diastolic blood pressure PP, pulse pressure BMI, body mass index BP, blood pressure.

§ P values for comparisons are from a Mann-Whitney U or χ 2 test.

P values indicate the significance of a sex×blood pressure group interaction in a linear model with Gaussian link or a geneneralized linear model with ordinal response and logit link function. Models also included main effect terms for sex and hypertension group (not shown).

Mean BP and Hypertension Prevalence

In the largest medical round (October 2008–2009), any observation of hypertension was followed with a confirmatory reading within a half hour. Mean BP for Tsimane men and women, respectively, was 113, 108 mmHg (SBP) 70, 66 mmHg (DBP) and 43, 41 mmHg (PP). This cross-sectional analysis shows a notable increase in SBP and PP with age for women and a very modest increase in SBP for men (Figure S1). Prevalence of hypertension was 3.9% for women and 5.2% for men (Figure S2). It was highest among women over age 70 years (30.4%). Isolated systolic hypertension accounted for 49.3% of hypertensive cases, and isolated diastolic accounted for 22.3%. Prehypertension prevalence was 17.4% for women and 29.1% for men.

Prevalence of hypertension declined substantially if we required additional observations of elevated BP in other rounds. Among people sampled ≥3 times, only 38% were hypertensive more than once, and only 1% were hypertensive for all of the readings (Table S1). Even among those sampled 8 times, 50% of those with a hypertensive measurement were hypertensive only once. It is, therefore, likely that the true prevalence of hypertension may be as low as one third the rates based on single measurements reported in Table S1 and preliminarily described in Reference 20. Among those sampled multiple times, frequency of ≥2 instances of hypertension was low (Figure 1). Only 7.7% and 27.3% of men and women, respectively, in the highest risk age category (aged ≥70 years) were hypertensive more than once, whereas an additional 18% of each sex were hypertensive only once. Overall, prevalence of repeat hypertension was 2.9% for both sexes.

Figure 1. Prevalence of hypertension by age and sex among those sampled at least twice. ☐, hyper only once ▩, hyper more than once.

Rise in BP With Age

We estimated age trajectories of SBP, DBP, and PP for Tsimane and a US comparison (National Health and Nutrition Examination Survey 2005–2006 Figure 2). Men's SBP is much flatter across adulthood than women's, whose SBP rises substantially around menopause. DBP increase with age is modest for women, whereas DBP decreases for men after age 60 years. This decrease in DBP is observed for both men and women in the U.S. PP increases for women after age 40 and less steeply for men after age 45. Despite these sex differences, Tsimane age profiles indicate substantially less change in BP with age than US age profiles, even after controlling for BMI (Figure 2). However, both populations show similarities, including lower SBP for women than men at younger ages and increasing BP in women after menopause. Although blunted, Tsimane males also show an increase in DBP early in life and a decrease later in life. PP increases at later ages in both populations.

Figure 2. Blood pressure (BP) by age and sex. Generalized additive models of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) for males (solid lines) and females (dashed lines), controlling for body mass index (BMI) and pregnancy status. Tsimane models are mixed models to control for repeated observations (n=5528 observations, 1749 individuals). National Health and Nutrition Examination Survey (NHANES) models are based on a single time point (n=7359). Both models are illustrated at BMI=25.84, which is the midpoint between mean BMI for Tsimane (23.67) and NHANES (28.00). Gray lines are 95% CIs for the mean.

The 2-stage mixed-modeling strategy tests for effects on both the intercept and rate of increase in BP for individuals (Tables 2 and S3). Stage 1 models main effects of predictors on BP, using random effects to control for repeated observations. Stage 2 assigns a slope to each individual consisting of the population slope for that age from stage 1 plus the individual's difference from the population mean obtained from the stage 1 random-effects model. These analyses include controls for sex, pregnancy status, season, BMI, Spanish fluency, years of schooling, and distance to San Borja. Substantial variability exists among individuals in ΔBP (Figure 3). Overall, SBP increases throughout life for women. Average ΔSBP increases significantly among women aged 40 to 55 years and then declines gradually (Figure 3A). The net ΔSBP for men increases from a negative slope to a positive one by the mid-30s, increases slightly for a few decades to a maximum of 2 mmHg per decade, and then declines after age 50 years (Figure 3B). ΔDBP is constant and positive at ≈1 mm per decade for women but declines continuously with age in men (Figure 3C and 3D). ΔPP shows a similar pattern as ΔSBP in women, given the lack of age-related change in ΔDBP. ΔPP changes little before age 40 years given similar changes in ΔSBP and ΔDBP (Figure 3E). For men, ΔPP increases from negative before age 40 years to positive after age 40 years and close to 0 after age 60 years (Figure 3F).

Table 2. Two-Stage Mixed Models

Stage 1 models have a random slope and intercept for each individual in the study, with blood pressure (BP) as the dependent variable. Stage 2 models use the individual random-effect slopes plus population main effect of age from stage 1 as the dependent variable. Age was included as a nonlinear thin-plate spline in both models. Only individuals with data for all of the variables and ≥2 observations were included (n=695 individuals n=2876 observations). For more details please see the online-only Data Supplement. BMI indicates body mass index SBP, systolic BP DBP, diastolic BP PP, pulse pressure.

§ Data are relative to no smoking.

‖ Data are relative to speaks no Spanish.

¶ Data are relative to wet season.

Figure 3. Change in systolic blood pressure (BP SBP A and B), diastolic BP (DBP C and D), and pulse pressure (PP E and F) per decade by sex and age. Points are ΔBP vs mean observation age (Table 2, step 1). Lines are spline fits and 95% CIs for the slopes as a function of mean observation age, estimated with a generalized additive model (Table 2, step 2).

Cross-Sectional Versus Longitudinal Analysis

Although analyses above include repeated measures, they are cross-sectional because they estimate the overall population pattern for a given segment of time. An explicit longitudinal analysis looks at within-individual changes. We estimated ΔBP for each individual with ≥5 years between first and last observation using linear regression models and controlling for season of measurement and pregnancy status. ΔBP varies somewhat among cross-sectional and longitudinal analyses, although less so when cross-sectional analyses are restricted to the same set of individuals with ≥5 observations (Table 3). Because of intraindividual lability of BP, SEs of longitudinally estimated slopes are much higher than those estimated cross-sectionally, and in many cases slopes were not significantly different from 0.

Table 3. Comparison of 10-y Increase in BP as Estimated From CS vs L Analyses

CS indicates cross-sectional L, longitudinal BP, blood pressure SBP, systolic BP DBP, diastolic BP PP, pulse pressure. CS slopes were estimated on both the full sample and a subset with repeated observations ≥5 years apart, controlling for season, pregnancy, repeated measures, and subject identification. For values from CS analyses, parameter estimates (β) are shown for values from L analyses, mean parameters (Mβ) are shown. Significance is given for a 1-sample t test for results from L analyses and for the model parameter from CS analyses.

Across ages, men had positive but moderate ΔSBPs, ranging from 0.32 mm per decade in longitudinal to 1.23 mm per decade in the restricted cross-sectional analyses. Women had higher overall ΔSBP, ranging from 1.81 to 3.08 mm per decade. Men had little net increase in ΔDBP, with estimates ranging from −2.99 mm per decade in longitudinal to 0.93 mm per decade in the cross-sectional analysis. Similarly, female ΔDBP ranged from −1.86 mm per decade in longitudinal to 0.95 mm per decade in cross-sectional analysis. PP increased the most in longitudinal analyses, 3.31 and 3.67 mm per decade, but this increase was modest in cross-sectional analysis, with −0.02 and 1.95 mm per decade for men and women, respectively.

After segregating the sample by age, cross-sectional and longitudinal analyses showed similarities but with notable exceptions. Men aged 20 to 39 years had significantly decreasing ΔPP in the cross-sectional model, including all Tsimane, but increasing ΔPP in the restricted sample. In all 3 of the models, male ΔPP increased between ages 40 and 59 years, but only ΔSBP in the full cross-sectional model increased significantly above 0. Male ΔDBP declined significantly in individuals aged ≥60 years in all of the analyses. Like men, women aged 20 to 39 years had increasing ΔPP in the restricted sample and no change in the full cross-sectional sample. ΔSBP increased in all 3 of the models, although not significantly in the longitudinal analysis. For women aged 40 to 59 years, ΔSBP, ΔDBP, and ΔPP increased in both cross-sectional analyses. Increases in ΔSBP and ΔPP in the longitudinal analysis were not statistically significant. Women aged ≥60 years showed increasing ΔSBP, declining ΔDBP, and increasing ΔPP, but only ΔPP changed significantly and only in the full cross-sectional sample.

Variance in BP

To test whether BP patterns were consistent for all of the individuals or appeared to affect subpopulations differentially, we examined differences in variance in BP and longitudinal slopes by sex, age, and population. Overall, variance in SBP, DBP, and PP was higher in women than in men and higher in Americans than in Tsimane, particularly after age 40 years (Figure 4 and Table S4). Variance in both sexes and populations increased with age both Tsimane and American women showed higher variance in BP with age. Examining longitudinal slopes, Tsimane women had higher variance over age 40 years, but variance did not increase significantly at age ≥60 years compared with ages 40 to 59 years (Table S4). Tsimane men's SBP variance increased after age 40 years, and men's variance in slope also increased after age 60 years. Tsimane men's variance in DBP did not change significantly with age, whereas Tsimane and American women's DBP and PP variance increased with age (Figures 4 and S4). Overall variance was greatest for SBP, and the greater variance with age among women is evident. By age 60 years, although mean and median slopes for women were positive for SBP and PP, a significant portion of women showed slopes ≤0.

Figure 4. Distribution of individual systolic blood pressure (BP ΔSBP A), diastolic BP (ΔDBP B), and pulse pressure (ΔPP C) per decade by sex and age. Females are shown on the left (gray) and males on the right (white). Only individuals with ≥2 measures and ≥5 years between their earliest and latest BP measures were included. Box plots show the first to third quartile range. Distributions are smoothed density plots. White circles indicate medians.

Effects of Modernization

We examined effects of modernization on SBP, DBP, and PP controlling for age, sex, season, and pregnancy status (Table 2, Stage 1). BMI was associated with higher SBP (β=0.61), DBP (β=0.39), and PP (β=0.25). BMI was not associated with significant differences in ΔBPs with age. Living farther from town was associated with lower SBP (β=−0.30 per 10 km) and a greater ΔPP (β=0.08 mm/10 years per 10 km). Fluent Spanish speakers had lower PP than those with no Spanish fluency (β=−1.8 mmHg). Individuals in the lowest smoking tertile had lower DBP than nonsmokers (β=−1.43), but other tertiles did not differ from nonsmokers. Smoking and Spanish fluency were not associated with significant ΔBPs, and schooling was not associated with significant changes in baseline BP or ΔBP.

Discussion

Age-related increases in BP are modest among Tsimane compared with Westerners. BP changes little with age among Tsimane men, whereas a larger increase occurs among Tsimane women. Such increases are not uniform across the population. Longitudinal analyses reveal variability in age-related slopes, and variability increases with age, particularly among women. Overall, hypertension prevalence is low among Tsimane, and point observations of hypertension are not sustained over time.

To place the Tsimane age-related increase in context, we compared Tsimane ΔSBP and ΔDBP with those from 52 populations from Intersalt, 21 a cross-sectional study of hypertension using standardized methodology among adults aged 20 to 59 years (Figure 5). Tsimane slopes were derived from a mixed model with the same controls over the age range 20 to 59 years. Tsimane ΔSBP and ΔDBP were among the lowest, comparable with those from 4 other subsistence populations, the Xingu and Yanomamo of Brazil, Papua New Guinean highlanders, and rural Kenyans. National populations show ΔSBPs that are 2 to 8 times higher and ΔDBPs that are 2 to 4 times higher than Tsimane. Given their median level of adult SBP and DBP, Tsimane ΔBPs were smaller than that predicted by the regression lines (Figure 5). Overall, Tsimane BP and ΔBPs were small compared with other populations, even after controlling for BMI (Figure S3).

Figure 5. Increase in (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) per decade. Cross-cultural sample includes 52 populations from the Intersalt study (ages 20–59 years). 21 Tsimane slope estimates are represented by black dots. Other populations inside ovals include the Brazilian Yanomamo and Xingu Amerindians, Papua New Guinea highlanders, and Kenyans.

Despite the minimal age-related increases in BP, Tsimane BP age profiles shared similarities with Western profiles. Women had lower BPs than men at young ages, but beyond age 50 years, women's BPs equaled men's. In addition, DBP declined at older ages across populations. Explanations for the late drop in DBP include “burned out” diastolic hypertension, reduced cardiac output, and increased large arterial stiffness. 6 Burned out hypertension seems unlikely given the DBP decrease in a population with minimal hypertension and longitudinal BP increase.

Effects of modernization were small and not consistent with the notion that greater exposure leads to poor health outcomes. Although no indicator of modernization predicted a greater age-related increase in BP, BMI had the most substantial effect on BP level. Cohort increases in BMI have been linked to reduced physical activity, poor diet, and other changes associated with modernization. 22 Indeed, >85% of hypertension diagnoses occur in overweight or obese individuals (BMI ≥25 kg/m 2 ) among Westerners. 23 It might be expected, therefore, that behavioral changes associated with modernization should impact BP primarily through an indicator of obesity, that is, BMI. BMI is almost universally positively and independently associated with morbidity and mortality from hypertension, cardiovascular, and other chronic diseases and type 2 diabetes mellitus. 24 Greater body mass increases blood volume and viscosity, impairs pressure natriuresis, and can lead to renal tubular sodium reabsorption. 25 Adipocytes also release angiotensinogen, a precursor of angiotensin.

The effect of a unit change in BMI on BP is similar among Tsimane and Americans (β=0.39, 0.13, and 0.26 for SBP, DBP, and PP from the National Health and Nutrition Examination Survey β=0.61, 0.39, and 0.25 for Tsimane), but Tsimane BMI did not increase substantially throughout adulthood. Although obesity was rare among Tsimane (5.6% of women and 1.6% men age ≥20 years), overweight was not uncommon, including 27.8% of women and 21.9% of men. Heavy smokers and moderate Spanish speakers with greater schooling were more likely to be overweight or obese (Table S6). However, BMI was not greater in villages closer to town (Table S7), nor was overweight and obesity more prevalent (Table S6). Even if the average Tsimane was obese, Tsimane BP would not resemble US patterns. Based on the model from Table 2, a Tsimane woman with US average BMI at ages 40 and 70 years would have SBPs of 113 and 117 mmHg, respectively, whereas an American woman with Tsimane average BMI at the same ages would have SBPs of 116 and 122 mmHg, respectively (Table S8).

Despite the significant relationship between BMI and BP among Tsimane, Tsimane display lower median SBP and DBP and lower ΔSBP and ΔDBP than expected based on comparative BMIs of 52 Intersalt populations (Figure S3). Based on regressions using all of the Intersalt populations, Tsimane ΔSBP and ΔDBP from ages 20 to 59 years should be 339% and 134% greater, respectively, given their median BMI of 23.5. One possibility for the low BP given Tsimane BMI is that higher BMI among lean, active forager-horticulturalists reflects greater muscle rather than fat mass. However, this is not the case BMI is highly correlated with body fat percentage in men and women across the BMI range (men, r=0.76, P<0.0001 women, r=0.55, P<0.0001 Figure S4). Body fat percentage per unit increase in BMI also appears similar among Tsimane and US adults (1.5% from BMI of 20–35 Figure S4 for Tsimane women Reference 26 for US women).

Unlike patterns documented in the developed world, 23 Tsimane BMI reached its peak by age 45 years and then declined by 1.0 kg/m 2 by age 70 years (Table S6), although body fat percentage increased with age (men r=0.27, P<0.0001 women, r=0.13, P<0.0001). So, although we find evidence that modernization may lead to higher BMI among Tsimane, only cumulative smoking increased with age, whereas schooling and Spanish fluency were greater among younger adults. The net effect is a decline in BMI at late ages and only a minimal age-related increase in BP.

Distance to town showed minimal effect on BP and a positive effect on PP rise with age. However, indicators of modernization, such as smoking, Spanish fluency, and schooling, showed no consistent effects on BP. This finding contrasts with many published patterns of “0-slope” populations that underwent rapid modernization, where mean BP increased and also rose with age. 11 A meta-analysis of effects of modernization on BP shows universal positive effects with similar effect sizes worldwide (≈4 mm higher for SBP and 3 mm for DBP, on average). 14 That study, however, did not examine modernization effects on the rate of BP increase. Migration and initial contact (<3 years) in a modernized setting had the greatest positive impacts on BP, more than BMI or other variables. This high level of modernization is not representative of the Tsimane at present. Few Tsimane live in towns, and even those living in the most modernized villages still actively practice horticulture, fishing, and hunting. Most Tsimane have not given up their traditional lifestyle. Their diet remains rich in potassium, fiber, and omega-3 fatty acids and low in saturated fat. 20 Perhaps the greatest differences across regions is in access to other market foods (eg, sugar, salt, and cooking oil), medical attention, and schools. A comparison of risk factors across regions does not show consistent high risk in more acculturated regions (Table S7). For example, whereas women near town and the mission show highest Spanish fluency, literacy, and schooling (Figure S5), women living downstream from San Borja show the highest body fat and BMI, whereas women living in remote villages smoke more (Table S7 and Figure S6). Despite increasing modernization, low hypertension prevalence and minimal age-related increase in BP among Tsimane are noteworthy given that Native Americans display higher susceptibility to hypertension they show similar genetic profiles affecting salt avidity and cardiovascular reactivity as high-risk African populations, despite recent descent from cold-adapted north Asian populations. 15 This genetic propensity with rising obesity and changing diets is likely responsible for rising levels of cardiovascular disease and metabolic disease among native North Americans. However, among North American Indians from the Strong Heart Study, BP increased substantially with age but was minimally affected by obesity despite cardiovascular disease being the leading cause of death 27 (but see Reference 28). North American Indians show similar rates of hypertension compared with other US groups. 28 The nontrivial prevalence of prehypertension among Tsimane does suggest that imminent changes in cardiovascular risk factors are likely if physical activity, diet, or other hypertension-promoting conditions increase over time. Among “partially acculturated” island-dwelling Kuna, BP is also low and does not rise with age, whereas Kuna migrants to Panama City show relatively high prevalence of hypertension and rising BP with age. 29

Finally, sex differences in Tsimane BP are striking. Most of the substantial rise in SBP and PP occurs in women, especially during the 40s and 50s (Figures S1 and 2–4). We find greater variation in women's BP and ΔBP with age (Figure 4 and Table S4). Unlike the sex profiles of BP among Westerners, Tsimane women have higher rates of hypertension and are at greater risk of BP-related morbidity than men. Although age profiles of BMI do not vary markedly by sex, body fat increases at a higher rate among women (Figure S4 17.2% versus 12.2% per decade). BMI also has a 61% greater effect on SBP in women than in men (β=1.16 versus 0.72 Table S5). Postmenopausal increases in BP have been documented among Westerners and have been attributed to declines in estradiol production. 30 Estradiol influences vascular tone and structure and endothelial vasodilation and might inhibit vascular response to arterial injury. 31

Strengths and Limitations

To our knowledge, the Tsimane are the only foraging-horticultural population sampled longitudinally. Their active lifestyle, lack of BP medication, and variable experience with modernization provided a unique opportunity to investigate BP change with age. Little bias is expected, because ≥90% of adults present were sampled per medical round. Few adults, however, were sampled ≥5 times, and the maximum time depth of the study was only 8 years. Although we include several measures of modernization, we did not consider its direct effects via individual-level measures of diet, physical activity, and other behavioral changes, although these are being collected in ongoing studies.

Perspectives

We found low levels of persistent hypertension and minimal age-related BP increase among Tsimane Amerindians compared with Westerners. Tsimane women were at greater risk of hypertension at late ages. Proximity to town affected SBP but not rate of BP increase in the predicted direction BMI impacted BP level, but not BP slope, with age. Many aspects of traditional diet and activities were preserved even among more modern Tsimane, suggesting that they have not yet experienced severe changes that would otherwise promote greater hypertension and cardiovascular disease. Prehypertension prevalence was moderate, suggesting that further changes in diet and behavior could place Tsimane at elevated risk.


Adrenaline

Adrenaline is a prototypical sympathomimetic drug (used as a template against which other drugs are compared) this is because it acts on both alpha and beta receptors. It produces its effects through the second messenger system.

On alpha 1 receptors, it acts through IP3 second messenger system by increasing Ca++ levels.

On alpha 2 receptors, it acts by decreasing the cAMP levels.

On beta 1, 2 and 3 receptors it acts by causing an increase in the cAMP levels.

Pharmacological Actions

CVS
Blood Pressure:

Adrenaline acts on both alpha and beta receptors, thus the blood is redistributed.

Arterial Pressure = Cardiac Output x Total Peripheral Resistance

Cardiac Output = Heart rate x Stroke volume

Beta 1 receptors stimulate the heart and produce a positive ionotropic (increased force of contraction) and a positive chronotropic (increased heart rate) effect.

Vasodilatation occurs in the limbs while vasoconstriction occurs elsewhere, beta 1 receptors cause vasodilatation in the heart, alpha receptors are also stimulated, and thus an interplay between alpha and beta receptors occurs. At physiological concentrations, beta receptors are stimulated first. At higher concentrations alpha receptors are stimulated first. Thus the total peripheral resistance either remains the same, increases or decreases, depending on the type of receptors stimulated.

The action of drugs depends on:

  1. Receptor type
  2. Affinity of drugs for receptors
  3. Intrinsic activity of drugs
  4. Compensatory responses (e.g. reflex bradycardia)

Systolic blood pressure, under adrenaline influence, is increased. The diastolic pressure may not increase, decrease or increase very slightly. It mainly depends on the total peripheral resistance, in excessive vasodilatation it may even fall.

The net result is that the pulse pressure gets widened.

Blood Vessels:

Blood vessels are constricted or dilated.

The skin, mucous membrane, kidney and pulmonary blood vessels constrict under the influence of adrenaline.

The skeletal muscle blood vessels are dilated.

Coronary blood flow increases due to:

  1. Intrinsic activity, by the release of adenosine, which causes vasodilatation.
  2. Beta 2 receptors may also be present.

Cerebral blood flow depends mostly on systolic pressure, but is auto regulated. It generally increases.

Heart

Due to positive chronotropic and positive ionotropic effect, the work load on the heart increases, this increases the oxygen consumption. Apart from this the conduction velocity also increases (positive dromotropic effect). The effective refractory period decreases. The excitability of the heart increases (positive bathmotropic effect). In higher doses, arrhythmias may occur. Positive lusiotropic effect is also seen (increase in calcium uptake by cardiomyocytes leading to increased myocardial relaxation).

ECG:

Adrenaline may produce ST elevation or depression. It may also produce flattening or inversion of T wave especially in individuals prone to heart diseases (above 40 yrs etc.). Both these findings indicate ischemia.

The coronary blood flow increases but the oxygen consumption is much more. There is thus relative ischemia.

Epinephrine Reversal or Vasomotor Reversal Phenomenon of Dale*

It states that “If alpha 1 blockers are given before administering epinephrine, there will be no increase in total peripheral resistance due to lack of vasoconstriction and there will be a fall in blood pressure due to decreased TPR”.

Eye:

The pupils are dilated. In the iris two muscles are present, dilator papillae (alpha 1 receptors) and sphincter papillae (muscarinic) are present.

  1. Adrenaline, by agonist action, produces mydriasis or dilatation of pupil.
  2. Alpha 1 receptors also act on the blood vessels, thus the conjunctiva becomes pale due to vasoconstriction.
  3. Reduction in intraocular pressure takes place.

Glaucoma is of two types open angle and narrow angle (shallow anterior chamber of eye). Normal intraocular pressure is 17-18 mmHg due to the aqueous humor secreted from ciliary processes. These secretions enter the anterior compartment of eye and drain through the canal of Schlemm. Episcleral plexus of brain is drained in to the systemic circulation. This route accounts for 80-90% of drainage. Uveoscleral pathway is the one in which fluid passes through the intercellular spaces among ciliary muscle fibers to enter the choroidal space.

Normal intraocular pressure can only be maintained by balance between the production and drainage of the fluid otherwise it may rise, leading to glaucoma. This may damage the optic nerve.

Adrenergic drugs and prodrugs like Dipevefrin were used in older days for open angle glaucoma. This drug acts by reducing the production and improving the drainage through the uveoscleral pathway. Vasoconstriction causes decreased production, while possible prostaglandins are released to improve the drainage.

GIT:

Adrenaline has a milder effect on GIT. This is the only place where both alpha and beta receptors produce the same effects. Smooth muscles relax resulting in decreased motility. Pyloric and ileocecal sphincters are constricted (alpha 1 effect).

Urinary Bladder

The detrusar muscles relax (beta effect). Trigone and sphincters are constricted. The smooth muscles of the prostate in male are constricted as well (alpha effect). There is, thus, hesitancy in voiding urine.

Uterus:

Acting on beta 2 receptors, adrenaline produces relaxation. In order to defer labour, beta 2 stimulants are used in the form of infusions for relaxation of uterine contractions. Beta 2 agonists are used adrenaline has the same effects as well.

In premature labour, fetus is given corticosteroids otherwise respiratory distress syndrome might develop.

Respiratory System:

In the older days adrenaline was used for status asthmaticus. It was injected subcutaneously in children suffering from bronchial asthma producing bronchodilatation. But adrenaline is non-selective in action. Albuterol and Salbutamol are used now. Vasoconstriction of respiratory mucosa and upper respiratory tract appears and has decongestion effect. Thus reducing respiratory tract secretions. This might be beneficial may be used in form of inhalation. Beta agonists are used now.

Central Nervous System

Adrenaline is a catecholamine and does not cross the blood brain barrier. At higher concentration person becomes apprehensive, restless and anxiety is visible as well as the feeling of doom. This is because of somatic manifestation of anxiety (as tachycardia, tremors occur because of adrenaline due to synchronous and enhanced firing and increased metabolism).

Anti allergic Effect

Adrenaline is the drug of choice in anaphylactic shock. Type 1 hypersensitivity occurs and histamine is released by mast cells. There are four types of histamines (H1,2,3,4), amongst which H1 and H2 are important. H1 is important because of respiratory tract effect of bronchoconstriction, laryngeal edema and generalized edema. By excessive dilatation by histamine, blood pressure decreases and may lead to shock. Effects of histamine are reversed by adrenaline injected subcutaneously, intramuscularly or intravenously in diluted form. It acts on both alpha 1(causing vasoconstriction and decreased plasma exudation) and alpha 2 receptors as well as beta 1 (increasing force of contraction of heart) and beta 2 (causing bronchodilatation) receptors. This is a good example of physiological antagonism. As a result total peripheral resistance is increased, resulting in increased blood pressure. Thus all effects of histamine are reversed.

In addition, adrenaline decreases the release of inflammatory mediators from mast cells. It is thus a wonderful anti allergic drug.

Metabolic Effects
  1. Beta 3 receptors are present in the lipocytes and adipose tissue. Adrenaline acts to cause breakdown of triglycerides into free fatty acids and glycerol. Adrenaline stimulates the triglyceride lipase which causes this breakdown.
  2. Increased glucose levels or hyperglycemia occurs due to :
    1. Insulin secretion as a whole is decreased. In beta cells of pancreas beta receptors increase the secretion, while alpha 2 receptors cause a decrease. Alpha 2 effect predominates.
    2. Decreased peripheral utilization
    3. Increased glucagon secretion (beta effect)
    4. Increased glycogenolysis (beta effect) in both liver and skeletal muscles.
    5. Reduction in potassium levels in the blood, increasing reuptake by skeletal muscles. As more potassium is released, therefore, by virtue of adrenaline more is transported back. There is a narrow range within which the potassium levels are maintained (3.5-5.5 mEq).
    Miscellaneous Effects:
    1. Effects on blood leukocytosis (increased neutrophils). Adrenaline causes de-margination of the neutrophils in the vessels, thus their concentration in circulation is increased.
    2. Increased coagubility because of increase in factor 5.
    3. Sweat glands are of two types:
      1. Thermoregulatory
      2. Non-thermoregulatory

      An increase in the secretion of non-thermoregulatory sweat glands takes place (mainly present in palms). These sweat glands are cholinergic.

      Adrenaline is acted upon by:

      First one acts then the other. Vanillyl mandelic acid (VMA) is excreted. Its quantity is estimated over 24 hours when there is doubt of tumor secreting adrenaline (e.g. pheocytochroma).

      Therapeutic Uses:

      In adults concentration used is in ampoules. It is 1 in 1000. About 0.3-0.5ml are used in adults. In children, concentration is same (1 in 1000), while dosage is calculated according to body weight i.e. 0.1 ml/kg body weight. But not more than 0.5 ml.

      Route:

      Subcutaneous, intramuscular, intravenous (in diluted form slowly, otherwise rapid rise is heart rate and hypertension results).

      1. Anaphylaxis
      2. Prolongation of local anesthetic activity

      a. Adrenaline produces vasoconstriction due to alpha 1 receptors, when combined with a local anesthetic, its effect is enhanced due to the fact that the drug stays in that particular area for a longer duration

      b. Total dose of local anesthetic may be reduced as stays for a longer duration

      c. Local anesthetic is generally used where surgical procedures are performed. If adrenaline is combined, vasoconstriction causes a reduction in bleeding.

      One particular anesthetic is cocaine, which should not be combined with adrenaline. Reuptake of nor-epinephrine is blocked by cocaine and thus noradrenaline stays for a longer duration prolonging its effects.

      3. Cardiac Resuscitation

      In cases of cardiac arrest, adrenaline may be injected intracardially into the ventricles to kick start the heart.

      4. Control of Capillary Bleeding

      In nasal operations, small plugs soaked in adrenaline are used to control bleeding by vasoconstriction.


      Venous Blood Pressure

      Venous pressure is the vascular pressure in a vein or the atria of the heart, and is much lower than arterial pressure.

      Learning Objectives

      Distinguish venous blood pressure from arterial blood pressure

      Key Takeaways

      Key Points

      • Venous pressure values are commonly 5 mmHg in the right atrium and 8 mmHg in the left atrium.
      • Several measurements of venous blood pressure exist in various locations within the heart, including central venous pressure, jugular venous pressure, and portal venous pressure.
      • The portal venous pressure is the blood pressure in the portal vein and is normally 5–10 mm Hg.
      • Variants of venous pressure include central venous pressure, which is a good approximation of right atrial pressure, which can then be used to calculate right ventricular end diastolic volume.
      • Neurogenic and hypovolemic shock can cause fainting. When the smooth muscles surrounding the veins become slack, the veins fill with the majority of the blood in the body, keeping blood away from the brain and causing unconsciousness.

      Key Terms

      • central venous pressure: The pressure of blood in the thoracic vena cava, near the right atrium of the heart, reflecting the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system.
      • jugular venous pressure: The indirectly-observed pressure over the venous system via visualization of the internal jugular vein.
      • venous system: The portion of the circulatory system composed of veins, which carry blood towards the heart.

      Blood pressure generally refers to the arterial pressure in the systemic circulation. However, measurement of pressures in the human venous system and the pulmonary vessels play an important role in intensive care medicine and are physiologically important in ensuring proper return of blood to the heart, maintaining flow in the closed circulatory system.

      The Human Venous System: Veins (from the Latin vena) are blood vessels that carry blood towards the heart. Veins differ from arteries in structure and function arteries are more muscular than veins, while veins are often closer to the skin and contain valves to help keep blood flowing toward the heart.

      Systemic Venous Pressure

      Venous pressure is the vascular pressure in a vein or the atria of the heart. It is much lower than arterial pressure, with common values of 5 mmHg in the right atrium and 8 mmHg in the left atrium. Variants of venous pressure include:

      1. Central venous pressure, a good approximation of right atrial pressure, which is a major determinant of right ventricular end diastolic volume.
      2. Jugular venous pressure (JVP), the indirectly observed pressure over the venous system. It can be useful in differentiating different forms of heart and lung disease.
      3. Portal venous pressure or the blood pressure in the portal vein. It is normally 5–10 mmHg.

      Vein Structure and Function

      In general, veins function to return deoxygenated blood to the heart, and are essentially tubes that collapse when their lumens are not filled with blood. Compared with arteries, the tunica media of veins, which contains smooth muscle or elastic fibers allowing for contraction, is much thinner, resulting in a compromised ability to deliver pressure. The actions of the skeletal-muscle pump and the thoracic pump of breathing during respiration aid in the generation of venous pressure and the return of blood to the heart.

      The pressure within the circulatory circuit as a whole is mean arterial pressure (MAP). This value is a function of the cardiac output (total blood pumped) and total peripheral resistance (TPR). TPR is primarily a function of the resistance of the systemic circulation. The resistance to flow generated by veins, due to their minimal ability to contract and reduce their diameter, means that regulation of blood pressure by veins is minimal in contrast to that of muscular vessels, primarily arterioles. The latter can actively contract, reduce diameter, and increase resistance and pressure. In addition, veins can easily distend or stretch. A vein’s ability to increase in diameter in response to a given blood volume also contributes to the very low pressures within this segment of the circulatory system.

      Pooling and Fainting

      Standing or sitting for a prolonged period of time can cause low venous return in the absence of the muscle pump, resulting in venous pooling (vascular) and shock. Fainting can occur, but usually baroreceptors within the aortic sinuses initiate a baroreflex, triggering angiotensin II and norepinephrine release and consequent vasoconstriction and heart rate increases to augment blood flow return.

      Neurogenic and hypovolemic shock can also cause fainting. The smooth muscles surrounding the veins become slack and the veins fill with the majority of the blood in the body, keeping blood away from the brain and causing unconsciousness. Jet pilots wear pressurized suits to help maintain their venous return and blood pressure, since high-speed maneuvers increase venous pooling in the legs. Pressure suits specifically squeeze the lower extremities, increasing venous return to the heart. This ensures that end diastolic volumes are maintained and that the brain will receive adequate blood, preventing loss of consciousness.