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What could an increase in systolic blood pressure and decrease in diastolic mean?

What could an increase in systolic blood pressure and decrease in diastolic mean?


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Sorry if this is a really simple question but my academic background is in completely different sciences. I recently made a computer game for an experiment that was related to anxiety and relaxation. One of the ways that I measured for success was to record participants blood pressure before and after they played the game.

There was a slight increase in systolic BP after playing the game, but not by a statistically significant amount. However the data shows a decrease in diastolic BP that is statistically significant. I've been trying to figure out why this might have happened but can't seem to find any answers. My brief overview of search engines and journals only seem to relate these changes to certain types of exercise. Which doesn't help as the participants of the experiment were asked to remain seated for 20 minutes by the time the second BP recording was made. Just wondering if anyone has any information in relation to relaxation techniques that might result in this pattern?

If it helps heart rate has mostly uniform throughout the experiment.


First, a couple of considerations

  • Heart rate (HR) is lower when seating, and even lower when lying. I assume that participants were seated when the first measure was taken.
  • Cardiac output is not constant during the day. Depending on the moment, some factors such as digestion have an impact in Cardiac output, so take that into account when carrying out the experiments.

Normal walking may cause that blood pressure pattern. I think that you should not consider the increase in systolic pressure if it is not significant, as something as simple as crossing your legs when seated can increase your systolic pressure and normally diastolic pressure provides more information for physicians. Relaxation techniques usually decrease heart rate, which can affect the blood pressure. However, the point in this case seems to be that HR remains constant. I suppose that Mean Arterial Pressure $(MAP)$ has decreased.

If we part from:

$ extit{MAP} = (CO cdot SVR) + CVP$ where $CO$ is cardiac output, $SVR$ is systemic vascular resistance and $CVP$ central venous pressure.

$CVP$ is usually depreciable. $CO$ is defined by $SV cdot HR$, where $SV$ is the stroke volume. Then, if the HR is constant, only $SV$ or $SVR$ could have changed. Maybe the heart is pulsating more vigorously, or a vasodilation is decreasing $SVR$. I find the latter more likely. However, I don't know why the smooth muscle could be relaxing. Make sure that heart rate is not changing and consider your sample size. I hope it helps, at least to focus you search on cardiac regulation. It is difficult to conclude anything without seeing the data but I tried to answer from my limited knowledge since I am not specialized in cardiac physiology.


Diastolic blood pressure: How low is too low?

Blood pressure consists of two numbers. Systolic pressure, the force exerted on blood vessels when the heart beats, is the upper number. Diastolic pressure, the force exerted when the heart is at rest, is on the bottom — in more ways than one. Systolic pressure attracts the lion’s share of attention from physicians and patients, says UAB cardiologist Jason Guichard, M.D., Ph.D.

“Physicians are busy people, and like it or not they often focus on a single number,” Guichard said. “Systolic blood pressure is the focus, and diastolic pressure is almost completely ignored.” That is a mistake, he argues. “The majority of your arteries feed your organs during systole. But your coronary arteries are different they are surrounding the aortic valve, so they get blood only when the aortic valve closes — and that happens in diastole.”

Diastolic pressure has been getting more attention lately, however, thanks in part to an influential paper in Hypertension, written in 2011 by Guichard and Ali Ahmed, M.D., then a professor of medicine in UAB’s Division of Gerontology, Geriatrics and Palliative Care and now the associate chief of staff for Health and Aging at the Veterans Affairs Medical Center in Washington, D.C. (Ahmed remains an adjunct faculty member at UAB.)

That paper coined a new term, “isolated diastolic hypotension,” which refers to a low diastolic blood pressure (less than 60 mm Hg) and a normal systolic pressure (above 100 mm Hg). Older adults who fit those conditions are at increased risk for developing new-onset heart failure, the researchers found.

“High blood pressure is a problem, but low blood pressure is also a problem,” Guichard said. That realization helped drive a 2014 decision by the panel members appointed to the Eighth Joint National Committee (JNC 8) to relax target blood pressure guidelines for those over 60 years old. [Read Guichard's take on "ideal blood pressure" and the new guidelines in this blog post.]

“Years ago and until recently, doctors were treating blood pressure so aggressively that many patients couldn’t even stand up without getting dizzy,” Guichard said. “We want to empower patients to know that you don’t have to drop those numbers all the way down to nothing, to the point where you can’t play with your grandkids or play golf or take a simple walk around the block because your blood pressure is so low. I think it’s important to raise awareness in this area, especially for older people.”

Jason Guichard Ahmed and Guichard are continuing to explore the mechanisms behind low diastolic pressure in more detail. Several new papers are pending, Guichard says. In the meantime, he sat down with The Mix to explain the dangers associated with low blood pressure.

Most people are trying to lower their blood pressure. What would you define as “too low,” and why is that a problem?

A diastolic blood pressure of somewhere between 90 and 60 is good in older folks. Once you start getting below 60, that makes people feel uncomfortable. A lot of older folks with low diastolic pressures get tired or dizzy and have frequent falls. Obviously, none of that is good news for people who are older, who potentially have brittle bones and other issues.

Your coronary arteries are fed during the diastolic phase. If you have a low diastolic pressure, it means you have a low coronary artery pressure, and that means your heart is going to lack blood and oxygen. That is what we call ischemia, and that kind of chronic, low-level ischemia may weaken the heart over time and potentially lead to heart failure.

What could cause a person to have low diastolic blood pressure?

Medications are a big one. There are some medicines that are culprits for lowering your diastolic blood pressure more than your systolic — specifically, a class of medications called alpha blockers, or central acting anti-hypertensive agents.

Another reason is age. As you get older, your vessels become a little more stiff, and that tends to raise your systolic pressure and lower your diastolic pressure.

It’s hard to reverse the aging process but one potential therapy is to find ways to allow your vessels to retain their elasticity — or, if they’ve lost it, maybe ways to gain that back.

The best current treatment is to lower dietary salt intake, which has been shown to be very closely linked with the elasticity of your vessels. The more salt you eat, the less elastic your vessels will be. Most peoples' salt intake is too high. Salt intake is a highly debated topic in medicine, but most believe that dietary salt intake of greater than 4 grams per day is too high, and less than 1.5 grams per day is too low. This depends on a person's age and underlying medical problems, but this range is a good rule of thumb. There is some data that the ideal salt intake for healthy people is around 3.6 grams per day, but again this is highly debated.

UAB’s hypertension group, led by Dr. Suzanne Oparil and Dr. David Calhoun, has detailed much of the basic science showing the effect of salt at a molecular level in the blood vessels. On the inside, your blood vessels are lined with a thin monolayer of endothelial cells. In an experimental setting, adding salt to these cells causes changes almost immediately. They become less reactive — that means they stiffen up — and lose their elasticity, which is what you actually see clinically.

Additionally, the stiffening of the vessels happens very soon after you take on a salt load during eating, which is very interesting.

Beyond changes in medications, what can people do to raise their diastolic pressure if it’s too low?

Lifestyle changes like diet and exercise can have immediate effects. Your inside changes much quicker than the mirror shows you. On the inside, you’re getting much more healthy by eating better, getting exercise, controlling your weight and not smoking.

Everyone thinks, “I’m going to have to do this for six months or a year before I see any changes.” That’s not true. The body is very dynamic. Within a few weeks, you can see the benefits of lifestyle change. In fact, with dietary changes in salt intake, you can see a difference in a day or two.

If someone does have low diastolic pressure, what should they — and their doctors — look for?

If they aren’t on medications that we could adjust, the important thing is close monitoring maybe seeing a patient more frequently in clinic and monitoring them closely for cardiovascular disease or heart failure symptoms.

Your original study in Hypertension got a lot of attention. What are you working on now?

We’re finalizing some papers that address two big criticisms of that study. The first criticism was that we were looking strictly, as the name suggests, at isolated diastolic hypotension. We didn’t really care at the time what the systolic pressure was doing but a high systolic pressure is a risk for heart failure, among other things. When we looked at the patients in our study, their systolic blood pressures were all relatively normal, and we adjusted for patients with a history of hypertension.

So we actually went back and redid the analysis, completely excluding people with hypertension. And the results still remained true. In fact, the association was even stronger.

The other criticism involved something called pulse pressure. That’s the difference between your systolic and diastolic blood pressure. And multiple studies have shown that a widened pulse pressure is also a risk factor for cardiovascular disease. Some fellow researchers said, “Really, all you’re looking at is just a wider pulse pressure. This isn’t necessarily novel — that’s been shown before.”

So we’ve actually looked at pulse pressure differences in all these patients and broken them down by differences in pulse pressure. And even when we adjusted for pulse pressure, the conclusion about the low diastolic pressure still rang true.

We actually looked at three different groups of pulse pressure — normal, wide and really wide. And it was true throughout. Low diastolic blood pressure increased one’s risk for heart failure.

You also have an interest in diastolic heart failure. What is that?

There are two different types of heart failure: one where the pumping function of the heart is abnormal — that is known as systolic heart failure — and one where the relaxation function is abnormal — that is known as diastolic heart failure. We have lots of medicines for, and experience treating, systolic heart failure, which is also called “heart failure with reduced ejection fraction” — everything from beta blockers, ACE inhibitors and ARBs to mineralocorticoid receptor antagonists and statins.

Diastolic heart failure, or “heart failure with preserved ejection fraction,” has no approved pharmacologic therapies to date. It was widely overlooked, to be honest, until about 10-15 years ago, when physicians realized that these poor patients were having terrible heart-failure symptoms but none of the classic objective measures of heart failure. In most cases, you can’t even tell the difference between a person with systolic and diastolic heart failure based on their symptoms. On the inside, however, their heart is pumping just fine the problem is their heart is stiff — it doesn’t relax as well as it should. That stiffness leads fluid to back up into the lungs and extremities and causes a lot of the symptoms that you have with systolic heart failure, but the pumping function of the heart is normal.

Now that there is an awareness of diastolic heart failure, we’re realizing that it is a very common problem. It looks like there are as many people with diastolic heart failure as with systolic heart failure. As a matter of fact, there may even be more people with diastolic heart failure.

It has become a heavily studied form of heart failure right now. Everyone is clamoring to get a medicine to help these patients, because it turns out to be very prevalent, and a lot of times they have the same morbidity and mortality as people with systolic heart failure.


What does diastolic hypertension mean?

Having high diastolic blood pressure is a sign that your blood vessels have become less elastic, hardened, and scarred. Blood pressure is not a static reading as it tends to fluctuate throughout the day with the normal rate of diastolic blood pressure ranging between 60 to 80 mmHg.

Having flexible blood vessels allows your body to appropriately manage oscillations in blood pressure. However, when your blood vessels are rigid, the chances of vessel rupture or obstruction is more likely to occur.


Systolic blood pressure

Elevation of systolic blood pressure predicts the risk of cardiovascular disease better than increases in diastolic blood pressure. 1 Although this was observed more than three decades ago, no attempt was made to translate this evidence into practice until in 1993, when a report of the fifth joint national committee of the United States for the detection, evaluation, and treatment of high blood pressure recognised isolated systolic hypertension as an important target for the control of blood pressure. 2 Nevertheless it is the elevation in systolic blood pressure that still limits our ability to control blood pressure to the recommended goal of less than 140/90 mm Hg. 3

Although associated with more variability in measurement, systolic blood pressure is easier to determine and allows more appropriate risk stratification than diastolic blood pressure. In a recent analysis of the Framingham heart study, knowing only the systolic blood pressure correctly classified the stage of blood pressure in 99% of adults over age 60 whereas knowing the diastolic blood pressure allowed only 66% to be classified correctly. 4 Isolated systolic hypertension is defined as a systolic blood pressure more than or equal to 140 mm Hg and a diastolic blood pressure less than 90 mm Hg and is the most common form of hypertension. 4 Its prevalence increases with age occurring in two thirds of people 65 years of age and three quarters of those over 75 years of age. 5

In people aged up to 50, both diastolic blood pressure and systolic blood pressure are independently associated with cardiovascular risk. At age 50 systolic blood pressure is far more important than the level of diastolic blood pressure in predicting the risk of coronary heart disease, left ventricular hypertrophy, congestive heart failure, renal failure, and mortality in people with hypertension. At age 60 years, however, as vascular compliance is reduced, an increasing systolic blood pressure and a lower diastolic blood pressure increase cardiovascular risk. 6

Age related physiological changes explain the frequent development of isolated systolic hypertension in older people. Younger people have a highly distensible aorta, which expands during systole and minimises any subsequent rise in blood pressure. Most older people, however, develop progressive stiffening of their arterial tree as they age, which leads to a continuous elevation in systolic blood pressure. 7 With the diastolic blood pressure remaining normal or decreasing with age, elderly people develop a widening of their pulse pressure (the difference between the systolic and the diastolic blood pressure). The elevation in systolic pressure increases left ventricular work and the risk of left ventricular hypertrophy, whereas the decrease in diastolic blood pressure may compromise coronary blood flow. 8 This widening of the pulse pressure at specified levels of systolic blood pressure, as assessed in the Framingham heart study, is associated with an increased risk of developing coronary heart disease. 6 In the absence of trial based evidence that uses pulse pressure narrowing as a target for improving outcome, however, lowering systolic blood pressure to a specific goal continues to be recommended as the major criterion for the management of hypertension, especially among middle aged and older people. 5

The benefits of treating systolic blood pressure have been well documented. Trials have shown significant reductions in stroke, coronary vascular disease, heart failure, and mortality when treating patients with isolated systolic hypertension (systolic blood pressure more than 150 or 160 mm Hg, diastolic blood pressure less than 90 mm Hg). 9 ,10 When systolic blood pressure was reduced by at least 20 mm Hg and to less than 160 mm Hg or less than 150 mm Hg, a 35-40 % reduction in stroke, a 50% reduction in heart failure, a 16% reduction in coronary events, and a 10-15% reduction in mortality occurred. 9 ,10 The benefits of treating stage 1 isolated systolic hypertension (140 mm Hg or greater with a diastolic blood pressure below 90 mm Hg) have not yet been shown in a clinical trial. Although none of the clinical trials achieved a systolic blood pressure below 140 mm Hg, a consensus statement implies that outcome should improve further when this goal is achieved. 11

Systolic blood pressure remains more difficult to control than diastolic blood pressure. 3 Nevertheless, doctors should be able to lower systolic blood pressure to less than 140 mm Hg in about 60% of patients. A diuretic and a dihydropyridine calcium antagonist are the only classes of drugs that have been tested as initial treatment in placebo controlled trials on isolated systolic hypertension. If a diuretic is used, potassium concentrations should be kept as close as possible to normal. 12 If not used initially, a thiazide diuretic should be included in most regimens to enhance the efficacy of other blood pressure lowering agents and reduce the risk of ischaemic stroke. w1 Since two or more agents are often necessary to reach the target of 140 mm Hg, caution should be exercised when lowering diastolic blood pressure to less than 55 mm Hg. w2

Lifestyle changes are also beneficial in controlling blood pressure in elderly patients. Restricting salt intake to 80 mmol daily reduces systolic blood pressure by 4.3 mm Hg and diastolic blood pressure by 2 mm Hg, and a combination of weight loss and salt restriction reduces blood pressure more than either strategy by itself and decreases the need for antihypertensive treatment. w3

Isolated systolic hypertension remains the most common form of hypertension and the most difficult to treat. w4 Substantial evidence supports the value of treating isolated systolic hypertension, and we must better inform doctors and the public about its consequences. It seems appropriate that we continually focus our efforts on more effective control of systolic blood pressure.


Clinical Significance

The research਍one by Blacher et al. has shown that pulse pressure is a significant risk factor in the development of heart disease. It has even been shown to be more of a determinant than the mean arterial pressure, which is the average blood pressure that a patient experiences in a single cardiac cycle. In fact, as little as a 10 mmHg increase in the pulse pressure increases the cardiovascular risk by as much as 20%. This finding was consistent in both Caucasian and Asian populations.[9]

Pulse pressure is also independently associated with an increased risk of developing atrial fibrillation. A study਍one by Mitchell਎t al. showed that patients with a pulse pressure ofꁀ mmHg or less developed atrial fibrillation at a rate of 5.6%, whereas patients with a pulse pressure greater than 61 mmHg developed atrial fibrillation at a rate of 23.3%. In fact, for every 20 mmHg increase in pulse pressure, the adjusted hazard ratio for developing atrial fibrillation is 1.28. This risk is independent of mean arterial pressure.[10]

Other research has focused on helping to maintain normal pulse pressure. One of the most effective ways to do this is to increase arterial compliance. According to Thorin-Trescases਎t al., endurance aerobic exercise is the only intervention that has shown to help mitigate age-related arterial stiffening by reducing age-related increases in collagen I and III and calcification. These same benefits were not seen with resistance training, such as bench press, as this decreases the arterial compliance and increases the pulse pressure.[11]

In addition to aerobic exercise training, Rajkumar et al. demonstrated that one਌ould also increase arterial compliance by increasing estrogen compounds (as in hormone replacement in post-menopausal women), increasing the consumption of n-3 fatty acids, and decreasing salt intake. There has also been some evidence that supports the notion that ACE inhibitors have beneficial arterial wall effects and may be of use.[12]


Abstract

Systolic and diastolic blood pressure thresholds, below which cardiovascular events increase, are widely debated. Using data from the SPRINT (Systolic Blood Pressure Intervention Trial), we evaluated the relation between systolic and diastolic pressure and cardiovascular events among 1519 participants with or 7574 without prior cardiovascular disease. Using Cox regression, we examined the composite risk of myocardial infarction, other acute coronary syndrome, stroke, heart failure, or cardiovascular death, and follow-up systolic and diastolic pressure were analyzed as time-dependent covariates for a median of 3.1 years. Models were adjusted for age, sex, baseline systolic pressure, body mass index, 10-year Framingham risk score, and estimated glomerular filtration rate. A J-shaped relationship with diastolic pressure was observed in both treatment arms in patients with or without cardiovascular disease (P nonlinearity≤0.002). When diastolic pressure fell <55 mm Hg, the hazards were at least 25% higher relative to 70 mm Hg (P=0.29). The hazard ratios (95% CI) of diastolic pressure <55 mm Hg versus 55 to 90 mm Hg were 1.68 (1.16–2.43), P value 0.006 and 1.52 (0.99–2.34), P value 0.06 in patients without and with prior cardiovascular disease, respectively. After adjusting for follow-up diastolic pressure, follow-up systolic pressure was not associated with the outcome in those without prior cardiovascular disease (P=0.64). In those with cardiovascular disease, adjusting for diastolic pressure, follow-up systolic pressure was associated with the risk in the intensive arm (hazard ratio per 10 mm Hg decrease, 0.86 95% CI, 0.75–0.99 P interaction=0.02). Although the observed J-shaped relationship may be because of reverse causality in the SPRINT population, we advise caution in aggressively lowering diastolic pressure.

Introduction

The landmark SPRINT (Systolic Blood Pressure Intervention Trial) determined that intensively lowering systolic blood pressure (SBP) to <120 mm Hg was associated with reduced mortality and cardiovascular events compared with standard SBP control of <140 mm Hg. 1 However, patients, healthcare providers, and guideline bodies have been reluctant to reduce BP to these lower targets given concern over increased risk of adverse events if BP falls too low. 2,3 This J-curve phenomenon, where the risk of adverse events increases when a lower BP threshold is breached, has been widely debated. Although physiologically it is known that at some lower BP threshold, organ perfusion becomes impaired and cardiovascular risk should increase, the exact BP threshold remains unclear. 4–10 Further, whether this threshold differs in patients with obstructive coronary disease who may be vulnerable to reduced coronary perfusion during diastole is a point of debate. 4,5 Most of the earlier studies did not prospectively target low enough BPs to determine a true nadir. 6–8 As such, these studies were unable to exclude reverse causation at lower extremes of BP, an epiphenomenon where achieved low diastolic pressure may reflect other conditions associated with cardiovascular risk including frailty, malignancy, malnourishment, or reduced systolic function. 11

The SPRINT trial therefore provides a unique opportunity to assess lower extremes of systolic and diastolic pressure in an at-risk population of patients without diabetes mellitus, history of stroke, or heart failure. 1 Using these data, we examined the relationship between lower SBP and diastolic BP (DBP) and risk for combined cardiovascular disease (CVD) events in those with and without CVD. We also examined clinical predictors of developing low DBP.

Methods

The SPRINT data were made available as part of a New England Journal of Medicine/National Heart, Lung, and Blood Institute initiative. Anonymized data were made publicly available at the New England Journal of Medicine/National Heart, Lung, and Blood Institute and can be accessed at https://biolincc.nhlbi.nih.gov/studies/sprint_pop/.

Study Population

The details of the SPRINT trial are published elsewhere. 12 In brief, this randomized, open-label, controlled trial included 9361 patients aged 50 years and older with a screening SBP of 130 to 180 mm Hg. Patients were included if they were 50 to 75 years with at least one of the following: an increased risk for CVD defined as history of clinical or subclinical CVD, chronic kidney disease (estimated glomerular filtration rate 20–60 mL min −1 1.73 m −2 ), 10-year Framingham CVD risk 13 of 15% or higher or if patients were aged 75 years or older. Patients were excluded from SPRINT if they had diabetes mellitus, heart failure, or previous stroke.

For this post hoc analysis, patients who experienced a cardiovascular event within 30 days of randomization, did not have any recorded BPs after randomization, or had missing key baseline characteristics were excluded. Therefore, follow-up was from 30 days post-randomization to the primary outcome, or noncardiovascular death, whichever came first. Patients were also stratified by history of clinical CVD using the SPRINT definition of clinical CVD (a prespecified subgroup in SPRINT). 12 Clinical CVD (other than stroke) was defined as any of (1) previous myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass grafting, carotid endarterectomy, carotid stenting, (2) peripheral artery disease with revascularization, (3) acute coronary syndrome with or without resting ECG change, ECG changes on a graded exercise test, or positive cardiac imaging study, (4) at least a 50% diameter stenosis of a coronary, carotid, or lower extremity artery, or (5) abdominal aortic aneurysm ≥5 cm with or without repair.

Procedures

SPRINT patients were randomized in 1:1 fashion to intensive BP lowering to a systolic target of <120 mm Hg versus standard SBP lowering of 135 to 139 mm Hg. There were no diastolic targets. Care providers followed a treatment algorithm emphasizing long-acting thiazide-type diuretics, but the algorithm did not restrict antihypertensive medication choices. The study was originally planned for a 5-year follow-up, but ended early because of clear evidence of treatment benefit (median follow-up, 3.26 years).

BP Measurements

A mean of 3 seated BPs was used to determine baseline and follow-up visit BPs using a fully automated validated BP device after a period of 5 minutes of quiet rest with the patient alone in the room. BP measurements were scheduled at baseline, months 1, 2, 3 and every 3 months until the study end.

Composite Cardiovascular Outcome

The primary outcome selected for this analysis was identical to the primary outcome in the SPRINT trial, namely a composite end point of MI, non-MI acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes. The definitions of MI and non-MI acute coronary syndrome used standard definitions including combination of symptom presentation, cardiac biomarker elevation, and ECG changes. Non-MI acute coronary syndrome required evidence of coronary ischemia but without meeting the definition of MI. Stroke is defined using standard definitions including symptoms and signs, as well as brain and cerebrovascular imaging. Heart failure was defined as diagnosed acute or subacute decompensated heart failure indicated by multiple signs of heart failure and requiring hospitalization or emergency department visit with intravenous treatment for heart failure. All outcomes were adjudicated, and the details are presented elsewhere. 1,12 We also examined (1) the composite of primary outcome and all-cause mortality as low BP is associated with noncardiac conditions and total mortality, 11 and (2) individual components of the primary outcome (online-only Data Supplement).

Statistical Analysis

To evaluate the relation between follow-up BP and risk of cardiovascular events, multivariable Cox regressions were performed separately for patients with or without a history of clinical CVD. For the primary outcome, if a patient died because of a noncardiovascular death without reaching the study outcome, the follow-up time was censored at the time of death. If the follow-up BP visits ended before the final event ascertainment, patients were censored at 6 months after the final BP visit. The achieved follow-up SBP and DBP at each visit were analyzed as time-dependent covariates. Because a nonlinear relationship between the BP measures and the log hazard was expected, the natural cubic spline was applied. Nonlinearity was evaluated using the likelihood ratio test. If nonlinearity was confirmed, the number of knots was then determined using the Akaike information criterion. 14 Two main models were constructed: the first, only examining follow-up systolic pressure and the second with both follow-up systolic and diastolic pressure. Our initial analysis indicated that the correlation between follow-up DBP and SBP was only moderate (r=0.54 Figure 1) therefore, it was feasible to include both SBP and DBP in the same model. Both models were adjusted for randomization group, baseline systolic pressure, and other prognostic factors selected using a backward stepwise procedure. Age, sex, body mass index, Framingham 10-year cardiovascular risk score, 13 and estimated glomerular filtration rate were adjusted in the final analyses. We also categorized the follow-up diastolic and systolic pressures in 3 discrete categories (<55, 55–90, and >90 mm Hg for DBP and ≤120, 121–150, and >150 mm Hg for SBP). Two-way interactions between the BP measures and treatment strategy were assessed. Analysis by treatment arm and interactions by sex and age are shown in the online-only Data Supplement. A P value <0.1 for interaction terms was considered significant.

Figure 1. Distribution of follow-up systolic blood pressure (SBP) and diastolic blood pressure (DBP) by treatment status and cardiovascular disease (CVD) history.

We evaluated risk predictors for a follow-up DBP measure falling <55 mm Hg, chosen based on risk level evaluated in the Cox regression analysis, using a logistic regression model with patient-specific random intercepts. Factors examined included sex, race (non-Hispanic black, Hispanic, non-Hispanic white, and other), study duration, and baseline factors (age, body mass index, smoking status [never, former, current]), baseline SBP and DBP, prior CVD, triglycerides (on the log scale), cholesterol, and creatinine (on the log scale). Interactions between treatment and other factors were examined.

All analyses were performed using RStudio (1.0.136), 15 with the package rms 16 and SAS 9.4 (Cary, NC). The SPRINT data were made available as part of a New England Journal of Medicine/National Heart, Lung, and Blood Institute initiative. This study was approved by the University of British Columbia ethics board.

Results

There were 7574 patients without CVD and 1519 patients with CVD in our analysis after exclusions 225 (2.9% 109 experienced an event or lost to follow-up <30 days 36 without at least 1 follow-up BP 80 with missing baseline data) and 43 (2.8% 26 experienced an event or lost to follow-up <30 days 8 without at least 1 follow-up BP 9 with missing baseline data) patients without and with clinical CVD, respectively, were excluded. There was no significant difference in proportion of those excluded by treatment assignment in those with and without CVD (P>0.81). Median follow-up time after exclusions was 3.1 years regardless of treatment arm and history of CVD, with an average of 13 follow-up BP visits.

Patients without CVD were younger, more likely to be female, or non-Hispanic black compared with those with CVD (Table 1). Those without CVD had a higher baseline BP and were taking fewer antihypertensive agents, but had a lower average 10-year Framingham risk score compared with those with CVD.

Table 1. Baseline Characteristics of the Study Participants*

CVD indicates cardiovascular disease GFR, glomerular filtration rate and HDL, high-density lipoprotein.

* Plus–minus values are means±SD. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for glucose to millimoles per liter, multiply by 0.05551.

† Race and ethnic group were self-reported.

‡ Black race includes Hispanic black and black as part of a multiracial identification.

§ Chronic kidney disease was defined as an estimated GFR of <60 mL min −1 1.73 m −2 of body surface area.

‖ The body mass index is the weight in kilograms divided by the square of the height in meters.

Follow-up SBP and DBP are shown in Figure 1 and Table 2. BPs were lower in those assigned intensive treatment versus standard treatment targets. Achieved SBP was also similar in those with and without CVD, but achieved DBP was lower in those with CVD compared with those without CVD. The correlations between baseline and SBP measured in the first 3 months after baseline was 0.24 and 0.13 for the later visits.

Table 2. Summary of Achieved SBP and DBP by Treatment Arm and Prior CVD Status (All Follow-Up Visits Pooled)

CVD indicates cardiovascular disease DBP, diastolic blood pressure and SBP, systolic blood pressure.

Cohort Without CVD

There were 3773 persons without CVD randomized to standard treatment (193 reached the primary outcome) and 3801 randomized to intensive treatment (138 reached the primary outcome).

Follow-Up SBP and the Primary Outcome

In the model without diastolic pressure, the relationship between follow-up SBP and the primary outcome was nonlinear (P=0.03), although a distinct J-shaped relationship was only observed in the standard group (Figure S1 in the online-only Data Supplement). When analyzing the follow-up SBP as a categorical variable, in the intensive BP-lowering group, achieving an SBP of ≤120 mm Hg was associated with a significant reduction in cardiovascular events, compared with achieved SBPs of 121 to 150 mm Hg in the standard arm (hazard ratio [HR], 0.64 95% CI, 0.48–0.86). In the standard treatment group, lowering SBP to ≤120 mm Hg was associated with a nonsignificant increase in cardiovascular events compared with achieved SBP of 121 to 150 mm Hg in the standard arm (HR, 1.38 95% CI, 0.92–2.06).

Follow-Up DBP and SBP and the Primary Outcome

When additionally accounting for follow-up diastolic pressure, there was no evidence of a nonlinear relationship (J curve) between follow-up SBP and the primary composite outcome. Therefore, a linear association was assumed, and the association was not significant (HR per 10 mm Hg decrease in follow-up SBP, 0.98 95% CI, 0.89–1.07 P=0.64).

As seen in Figure 2 (left), there was a J-shaped association between DBP and the composite cardiovascular outcome regardless of intensive or standard treatment strategy (P nonlinearity<0.001 P interaction=0.47). When plotted by treatment arm (Figure S2, left), the patterns were similar in both arms. As noted in Figure 2, the hazards increased when DBP was <55 or >95 mm Hg (ie, ≈25% higher hazard compared with 70 mm Hg). When considering DBP as a categorical variable, the HRs of DBP <55 and >90 mm Hg relative to DBP between 55 and 90 mm Hg were 1.68 (95% CI, 1.16–2.43) and 1.45 (95% CI, 0.89–2.35), respectively.

Figure 2. Association between diastolic blood pressure (DBP) and the composite cardiovascular outcome according to history of cardiovascular disease (CVD). Hazard ratios and 95% confidence intervals of the composite cardiovascular outcome for a range of follow-up diastolic pressure (left, for subjects without history of CVD and [right] for patients with CVD). Model was adjusted for treatment arm, baseline systolic blood pressure (SBP), follow-up SBP, age, sex, body mass index, Framingham 10-year risk score, estimated glomerular filtration rate.

Cohort With CVD

There were 754 persons with CVD randomized to standard treatment (93 reached the primary outcome) and 765 randomized to intensive treatment (83 reached the primary outcome).

Follow-Up SBP and the Primary Outcome

In the model without diastolic pressure, there was no evidence of a J curve between follow-up SBP and the primary composite outcome. Therefore, a linear association was assumed. The effect of follow-up SBP on the composite cardiovascular end point differed by treatment assignment (P interaction=0.05). In the standard treatment group, the hazard did not change significantly with follow-up SBP (HR per 10 mm Hg decrease, 1.06 95% CI, 0.92–1.22 P=0.44). However, in the intensive treatment group, the hazard of developing a cardiovascular event decreased with decreasing follow-up SBP (HR per 10 mm Hg decrease, 0.87 95% CI, 0.77–1.00 P=0.04). As a result, the treatment benefit was more evident among those achieved a lower SBP (intensive versus standard arm HR, 0.74 95% CI, 0.51–1.07 at 120 mm Hg HR, 1.59 95% CI, 0.84–3.02 at 160 mm Hg).

Follow-Up DBP and SBP and the Primary Outcome

After including follow-up DBP, the association between follow-up SBP and the primary composite outcome was similar to the model with follow-up SBP alone.

As seen in Figure 2 (right), there was a J-shaped association between DBP and the composite cardiovascular outcome (P nonlinearity=0.002). The pattern was similar in both the intensive and standard treatment strategy groups (P interaction=0.75 Figure S2, right). The hazard increased when DBP was >85 or <55 mm Hg. When considering diastolic pressure as a categorical variable, the HRs of DBP <55 and >90 mm Hg relative to DBP between 55 and 90 mm Hg were 1.52 (95% CI, 0.99–2.34) and 0.95 (95% CI, 0.37–2.40), respectively. Of note, a similar J-shaped relationship in the primary outcome was observed when CVD and non-CVD patients were combined (P nonlinearity<0.0001).

Supplementary Analysis

There was a significant interaction between age and follow-up DBP, but not sex (Figure S3). The analysis of the primary outcome and all-cause mortality also demonstrated a nonlinear J-shaped curve with follow-up DBP (data not shown) and for the individual end points of MI and heart failure (Table S1 Figures S4 through S6).

Predictors of Low DBP (<55 mm Hg)

As seen in Figure 3, a greater proportion of visits fell <55 mm Hg in the intensive arm (9.22%) than the standard arm (3.42%).

Figure 3. Proportion of participants with diastolic blood pressure (DBP) <55 mm Hg by study visit.

A lower baseline DBP increased the odds, whereas a higher baseline SBP with a low DBP (widened pulse pressure) increased the odds of the DBP falling <55 mm Hg (Figure S7). Other baseline predictors are presented in Table 3 (and by treatment Table S2). There was also an interaction between treatment and study duration (P interaction<0.001). Odds ratio of intensive versus standard was 4.42 (95% CI, 3.87–5.04) at 6 months, increasing to 6.24 (95% CI, 5.50–7.08) at 2 years.

Table 3. OR and 95% CIs of Baseline Factors for Falling Below a DBP of 55 mm Hg

DBP indicates diastolic blood pressure and OR, odds ratio.

* Based on a multivariate logistic regression with random intercepts. Out of 119 384 visits from 9078 participants that contributed to the analysis, 7573 follow-up DBPs from 2350 participants were <55 mm Hg.

Discussion

This study demonstrated a J-shaped relationship between DBP and risk of increased cardiovascular events <55 and >95 mm Hg. This pattern was similarly observed in the SPRINT patient population with a history of clinical CVD but at an upper diastolic threshold of 85 mm Hg. When taking account of DBP, there was no evidence of a J-shaped relationship between follow-up SBP and cardiovascular risk. Predictors of achieving a diastolic pressure of ≤55 mm Hg included lower baseline diastolic pressure <70 mm Hg, higher baseline SBP when accompanied by a low baseline DBP, male sex, older age, history of CVD, and elevated baseline creatinine.

Many observational studies and post hoc analyses of achieved BP in randomized controlled trials demonstrated a J- or U-shaped relationship between DBP and various cardiovascular outcomes. 6–9 However, the nadir diastolic pressures from these studies were considerably higher than identified in our analysis and generally ranged from 70 to 85 mm Hg. Further, studies predominantly identified a J curve in patients with coronary disease. 7,10,17 Our analysis identified a J-curve relationship with follow-up diastolic pressure in those with and without CVD <55 mm Hg. The CLARIFY international cohort study (The Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease) 10 and INVEST study (The International Verapamil-Trandolapril Study) 7 of patients with stable coronary disease found that cardiovascular risk doubled when DBP was <60 and 70 mm Hg, respectively. The SYST-EUR trial (Systolic Hypertension in Europe) of 4695 elderly persons targeted an SBP to <150 mm Hg and also demonstrated a J curve for diastolic pressure <70 mm Hg but only in patients with coronary disease. 9 However, in INVEST and other trials, the target BP in patients without diabetes mellitus was <140/90 mm Hg so achieving a diastolic pressure of <70 mm Hg may have been attributed to reverse causation or arterial stiffness and widened pulse pressure. The HOT trial (Hypertension Optimal Treatment), unlike previous trials, did prospectively target lowering DBP to ≤80, ≤85, and ≤90 mm Hg. 8 The HOT trial also demonstrated an increase in MI only with diastolic pressures <80 mm Hg in the subset of patients with coronary disease. The reasons for the higher DBP thresholds identified in previous analyses compared with our current analysis may be because of trial procedural differences. The baseline diastolic pressure in these earlier studies were considerably higher than in the SPRINT study, ranging from ≈85 mm Hg in INVEST and SYST-EUR to 105 mm Hg in the HOT trial. 7–9 Of note, the delta change in DBP of 25 mm Hg in the HOT trial associated with increased cardiovascular risk was analogous to our reduction of 23 mm Hg also associated with increased cardiovascular risk. The SPRINT trial used a mean of 3 unattended fully automated BP measurements, whereas other studies used casual office readings 10 or a mean of 2 seated attended BPs measured by research staff using oscillometric or auscultatory methods. The difference in BPs between such methods can be 5 to 10 mm Hg lower with the unattended BP measures and unattended fully automated oscillometric measure compared with manual office BP readings or readings conducted when others are present or talking. 18,19 Another possibility is that the extent of coronary artery disease may have been different in the SPRINT trial population compared with HOT and INVEST patients. Patients with more minimally obstructing coronary artery disease were likely included in SPRINT as SPRINT included persons with only coronary artery calcification or possibly had effective coronary revascularization treatments (percutaneous coronary intervention) or coronary artery bypass grafting than was available at the times of HOT or INVEST.

Few studies examining the J-curve phenomena also evaluated the combined effect of lowering SBP and DBP on cardiovascular outcomes. The INVEST study identified that the nadir of SBP was 119 mm Hg and the CLARIFY cohort identified an increased risk of CV events below a systolic pressure of 120 mm Hg. The J curve for the systolic pressure was less evident compared with the DBP curve, an observation similar to our analysis. Our findings of additional linear benefit of lowering systolic pressure after adjusting for diastolic pressure in those with CVD also confirm previous findings. 6 In an analysis of the Framingham data, evaluation of both systolic and diastolic pressures better predicted future cardiovascular events compared with either alone. 6 After adjusting for diastolic pressure, cardiovascular risk decreased with decreasing systolic pressure. 6

The pathophysiologic underpinnings of the J- or U-shaped relationship between diastolic pressure and CVD risk are likely multifold. 4,5 DBP is a major determinant of coronary blood flow as coronary perfusion occurs during diastole. As noted, we observed a J-shaped relationship between MI and heart failure and low achieved diastolic pressure. Also, the J- or U-shaped relationship may result from arterial stiffness reflected in a widened pulse pressure and impaired coronary perfusion as the retrograde aortic wave returns during late systole rather than diastole, leading to increased cardiovascular risk. Patients in the SPRINT trial may have had more arterial stiffness given their advanced age and high prevalence of chronic kidney disease even among those without documented CVD. Other confounding factors such as heart failure, malnutrition, or malignancy may also contribute to the J-shaped relationship between low diastolic pressure and the composite cardiovascular events. Although heart failure patients were excluded from SPRINT, in a mediation analysis using SPRINT data, Stensrud and Strohmaier 20 determined that confounding factors played an indirect and direct role in the J-shaped relationship. However, this analysis did not include data from the first year of the study. Our findings using the totality of data adjusting for multiple confounders demonstrated a J curve with individual end points of MI, heart failure, and our composite cardiovascular outcome.

The strengths of this analysis include accurate measurement of BP using unattended automated BP measures, use of data from a large clinical trial with prospective intensive low BP targets that allow further exploration of lower diastolic pressure and CVD risk, and the inclusion of elderly patients with and without a history of clinical CVD. However, there are several limitations to note. First, DBPs were not explicitly targeted in the SPRINT trial. As such, very low achieved diastolic pressures may reflect some reverse causation that we were not able to eliminate. We observed that patients with achieved DBP <55 mm Hg were associated with higher baseline cardiovascular risk burden than patients who did not have follow-up DBP <55 mm Hg (Table 3). However, mean follow-up diastolic and systolic pressures in this study were considerably lower in SPRINT compared with earlier studies. There may be residual confounding where we were unable to account for issues of malnutrition or malignancy that may have distorted the relationship between low DBP and outcomes. Further, there may be target organ heterogeneity where lower BP may have differential effects on cardiac end points compared with stroke end points. When we additionally analyzed total mortality, the threshold of diastolic pressure was generally unchanged. This analysis did not include other end points such as emergency department visits for hypotension, acute kidney injury, or injurious falls that may occur at very low diastolic pressures as well. Finally, the seated BP measurements used in SPRINT, unattended fully automated devices, may differ from some clinician offices, and therefore, the results of this analysis may not be generalized when using other BP measurement techniques.

Perspectives

In conclusion, intensive BP lowering in patients who have hypertension, but do not have diabetes mellitus, stroke, or heart failure, may increase cardiovascular risk if the diastolic pressure falls to ≤55 mm Hg. Although the observed J-shaped relationship might be because of reverse causality, we advise that clinicians should use caution when try to achieve SPRINT intensive targets especially among those at risk including men, older patients, those with CVD, those with low baseline diastolic pressure, and those with elevated creatinine. These data also suggest that there is a group of patients with CVD, perhaps those with effective myocardial reperfusion, in whom DBP lowering does not produce a greater risk than persons without CVD when DBP is measured as <60 mm Hg using unattended, fully automated BP devices with proper measurement technique.

Acknowledgments

This research used SPRINT (Systolic Blood Pressure Intervention Trial) Primary Outcome Paper Research Materials obtained form the Biologic Specimen and Data Repository Information Coordinating Center of the National Heart, Lung, and Blood Institute. We thank the rest of the ICVHealth Biostatistic team: May K. Lee, Defen Peng, Maja Grubisic, and Patrick Daniele, for their contribution to the data analysis and helpful input, and Mona Izadengahdar and Melissa Pak for their comments and help with ethics.


Abstract

Abstract—We compared systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP) in predicting the risk of cardiovascular disease (CVD), stratifying results at age 60 years, when DBP decreases while SBP continues to increase. We prospectively followed 11 150 male physicians with no history of CVD or antihypertensive treatment through the 2-year questionnaire, after which follow-up began. Reported blood pressure was averaged from both the baseline and 2-year questionnaires. During a median follow-up of 10.8 years, there were 905 cases of incident CVD. For men aged <60 years (n=8743), those in the highest versus lowest quartiles of average SBP (≥130 versus <116 mm Hg), DBP (≥81 versus <73 mm Hg), and MAP (≥97 versus <88 mm Hg) had relative risks (RRs) of CVD of 2.16, 2.23, and 2.52, respectively. Models with average MAP and PP did not add information compared with models with MAP alone (P>0.05). For men aged ≥60 years (n=2407), those in the highest versus lowest quartiles of average SBP (≥135 versus <120 mm Hg), PP (≥55 versus <44 mm Hg), and MAP (≥99 versus <91 mm Hg) had RRs of CVD of 1.69, 1.83, and 1.43, respectively. The addition of other blood pressure measures did not add information compared with average SBP or PP alone (all P>0.05). These data suggest that average SBP, DBP, and MAP strongly predict CVD among younger men, whereas either average SBP or PP predicts CVD among older men. More research should distinguish whether MAP, highly correlated with SBP and DBP, better predicts CVD.

The positive association between either systolic blood pressure (SBP) or diastolic blood pressure (DBP) and the risk of cardiovascular disease (CVD) is well established. 1 Blood pressure is also characterized by its pulsatile and steady components. 2 3 4 The pulsatile component, estimated by pulse pressure (PP), represents blood pressure variation and is affected by left ventricular ejection fraction, large-artery stiffness, early pulse wave reduction, and heart rate. 5 The steady component, estimated by mean arterial pressure (MAP), is a function of left ventricular contractility, heart rate, and vascular resistance and elasticity averaged over time. 2 6

It remains unclear which measures of blood pressure, either alone or in combination, best predict the risk of CVD. Data from the Framingham Heart Study 5 7 8 and other studies 9 10 indicate that SBP increases continuously across all age groups, whereas DBP increases until age 60 years and then begins to decrease steadily. As a result, PP may become a more important blood pressure measure associated with CVD in older individuals. 11 In addition, MAP has not been extensively studied, with positive associations in some, 12 13 14 but not all, 15 studies with CVD.

Therefore, we considered the use of SBP, DBP, PP, and MAP in a large cohort of men aged 40 to 84 years at baseline with no history of antihypertensive treatment. Using self-reported average blood pressure values on the baseline and 2-year questionnaires, we compared the associations of each blood pressure measure with the risk of incident CVD. We further examined potential differences in CVD risk by age dichotomized at 60 years, when DBP levels decrease while SBP continues to increase. 3 5

Methods

Study Population and Data Collection

The subjects and methods of the Physicians’ Health Study, a 2×2 factorial trial of aspirin and β-carotene for the primary prevention of CVD or cancer, have been described previously. 16 17 Briefly, 22 071 US male physicians, aged 40 to 84 years at entry, were enrolled and were free from prior myocardial infarction (MI), stroke, transient ischemic attack, cancer (except non-melanoma skin cancer), current renal or liver disease, peptic ulcer, and gout. Among the 22 071 randomized men, subjects were excluded if they had CVD (n=520), any past or current history of antihypertensive medication use (n=3460), or any missing data on blood pressure (n=4540) or antihypertensive medication use (n=2401) on either the baseline or 2-year questionnaires. These exclusions resulted in a study population of 11 150 men.

Self-reported blood pressure is expected to be reliable and valid, since a single measurement of self-reported blood pressure in a different study of physicians was highly correlated with measured SBP (r=0.72) and DBP (r=0.60). 18 Another study of the agreement of measured and self-reported blood pressure found a correlation similar to that for 2 measurements of blood pressure within a year. 19 We considered 2 other blood pressure measurements besides SBP and DBP. First, we calculated the PP, defined as SBP minus DBP. Second, we calculated the MAP as 1/3(SBP)+2/3(DBP). The average of the baseline and 2-year blood pressure values was used to further minimize any potential misclassification in self-reported blood pressure. On the baseline questionnaire, participants reported other coronary risk factors, including age, smoking status, alcohol use, frequency of vigorous exercise, history of diabetes mellitus, and parental history of MI at <60 years. Body mass index (in kg/m 2 ) was calculated from height and weight.

Follow-up of the 11 150 participants began after completion of the 2-year questionnaire. On annual follow-up questionnaires, participants were asked whether they had experienced any CVD event since the return of the last questionnaire. CVD events included MI, angina pectoris, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, stroke, and cardiovascular death. For men reporting MI or stroke and for reported deaths, relevant medical records were obtained from >95% of the participants. Nonfatal MI was diagnosed with the use of World Health Organization criteria. 20 Nonfatal stroke was defined as a typical neurological deficit, sudden or rapid in onset, lasting >24 hours. CVD death was documented by convincing evidence of a cardiovascular mechanism from death certificates and medical records. All analyses are based on the first CVD event. At the end of follow-up, 99.2% of men still provided morbidity information mortality follow-up was 99.99% complete. 17 In all, 905 incident CVD cases occurred over a median follow-up of 10.8 years (maximum, 11.2 years).

Data Analysis

All analyses were stratified a priori by baseline ages of <60 years (n=8743) and ≥60 years (n=2407). We first determined the mean values or proportions of baseline coronary risk factors according to each group of men. Next, we examined the blood pressure distributions in each subgroup of men. Stratum-specific Spearman correlation coefficients were also computed among the 4 measures of blood pressure.

Two separate analysis strategies sought to determine which measures of average blood pressure predicted the risk of CVD. We first compared equivalent multivariate Cox proportional hazards models that only differed by the measures of average blood pressure used. Seven main models were compared, including SBP only, DBP only, both SBP and DBP, PP only, both PP and DBP, MAP only, and both PP and MAP. Other joint models included SBP and PP, SBP and MAP, and DBP and MAP. Models included terms for age (years), body mass index (kg/m 2 ), randomized aspirin treatment (yes, no), randomized β-carotene treatment (yes, no), smoking status (never, past, current <1 pack/d, current ≥1 packs/d), vigorous exercise ≥1/wk (yes, no), alcohol consumption (<1 drink/wk, 1 to 6 drinks/wk, ≥1 drink/d), parental history of MI at <60 years (yes, no), and history of diabetes mellitus (yes, no). Use of finer categories of physical activity did not appreciably change the results. Although we did not control for self-reported lipid levels because data were missing in >10% of participants, 21 additional control for history of hyperlipidemia (self-reported or measured cholesterol >260 mg/dL) had little effect on the results. We calculated relative risks (RRs) and 95% CIs, assuming a 10-mm Hg increase in each blood pressure measure. All probability values were 2-tailed α=0.05. Nested blood pressure models were compared with the χ 2 test statistic from likelihood ratio tests.

Our second analysis strategy examined the individual effects of average SBP, DBP, PP, and MAP. Each blood pressure measure was categorized into quartiles for each subgroup of men. Cox proportional hazards models were used to calculate the RR of CVD, with the first quartile as the reference group. We also compared the ≥95th versus <25th percentiles. Multivariate models adjusted for the same coronary risk factors as before. The assumption of proportional hazards was confirmed in all models (all P>0.05) by Wald tests for the interaction of time with each measure of blood pressure. A linear trend across quartiles of blood pressure was tested with an ordinal variable, using median blood pressure levels within each quartile.

We also considered joint models of average SBP and DBP. Average SBP was categorized into <120, 120 to <130, 130 to <140, and ≥140 mm Hg, and average DBP was categorized into <70, 70 to <80, 80 to <90, and ≥90 mm Hg. The reference group included men with average SBP <120 mm Hg and average DBP <70 mm Hg. In sensitivity analyses, we considered other age cut points besides age 60 years. Separate multivariate models for each blood pressure measure were considered for men aged 40 to 49, 50 to 59, 60 to 69, and ≥70 years. Effect modification by age was assessed by examining the interaction between age (classified as an ordinal variable using median values from categories of 40 to 49, 50 to 59, 60 to 69, and ≥70 years) and each average blood pressure measure in multivariate models. We then examined whether the association between blood pressure and risk of CVD was similar for men with any history of hypertension treatment. Finally, the RRs for stroke (200 cases) were compared with the overall results for CVD.

Results

The mean (±SD) levels of average SBP, DBP, PP, and MAP for all 11 150 men (mean age, 52.3 years) were 124.1±11.1, 77.5±7.1, 46.6±8.8, and 93.0±7.6 mm Hg, respectively. Table 1 compares the blood pressure parameters and other baseline characteristics of men aged <60 and ≥60 years. As expected, men aged ≥60 years had higher levels of average SBP, PP, and MAP than men aged <60 years. Average DBP in men aged ≥60 years was similar to that in men aged <60 years. There were 5.3% and 16.8% of men aged <60 and ≥60 years, respectively, who had an average SBP ≥140 mm Hg or DBP ≥90 mm Hg despite reporting no history of antihypertensive treatment.

Spearman correlations between average SBP and DBP were 0.70 and 0.61 in men aged <60 and ≥60 years (both P<0.001). Average SBP and DBP were each highly correlated with MAP, with Spearman correlations ranging from 0.88 to 0.94 (all P<0.001) in all men. Average DBP was weakly correlated with PP, with Spearman correlations of 0.03 and 0.06 in men aged <60 and ≥60 years, respectively. All other combinations of blood pressure measures were highly correlated.

During 112 384 person-years of follow-up (median follow-up, 10.8 years), we identified 905 total cases (<60 years, 509 cases ≥60 years, 396 cases) of incident CVD. To reduce any potential bias due to underlying illnesses that may have affected their blood pressure levels, the exclusion of men with CVD during the first 3 years of follow-up did not materially alter the results. Additional adjustment for coronary risk factors other than age had a small relative impact on the RRs for blood pressure. There were 204 men (22 cases of CVD) who were excluded from multivariate models because of missing coronary risk factor data besides age however, a comparison of age-adjusted models with and without these subjects did not affect the RRs. For all Cox proportional hazards models in Tables 2 and 3 , adjustment for coronary risk factors introduced 12 degrees of freedom (df). Average blood pressure measures were then added to the multivariate model as follows: model 1, SBP model 2, DBP model 3, SBP and DBP model 4, PP model 5, DBP and PP model 6, MAP and model 7, PP and MAP.

Among men aged <60 years, the addition of any single measure of blood pressure added significantly to the multivariate model (all P<0.05 with 1 df) (Table 2 ). An increase of 10 mm Hg in average SBP, DBP, PP, and MAP had corresponding RRs of 1.31, 1.46, 1.23, and 1.48, respectively. In model 3, including both SBP and DBP did not add information compared with SBP alone (χ 2 =2.96, 1 df, P=0.09) but did add information compared with DBP alone (χ 2 =8.53, 1 df, P=0.003). Finally, a model with average MAP alone was virtually as good as models with MAP and either SBP, DBP, or PP (all P>0.05). In model 5, including both DBP and PP did add information compared with either DBP or PP alone (both P<0.05).

Among men aged ≥60 years, the addition of average SBP, PP, and MAP added significantly to the multivariate model (all P<0.05 with 1 df) (Table 3 ), with corresponding RRs for 10-mm Hg increases in average SBP, PP, and MAP of 1.21, 1.24, and 1.28, respectively. Average DBP was not significantly associated with the risk of CVD in men aged ≥60 years. In model 3, including both SBP and DBP did not add significantly to the model 1 with SBP alone (χ 2 =0.57, 1 df, P=0.45). In addition, the parameter estimate for average DBP was essentially zero. Models with SBP or PP alone were not improved with the addition of any other blood pressure measure (all P>0.05). The RRs for a model with both SBP and MAP were 1.29 and 0.89, respectively.

We next examined similar multivariate models in Table 4 but based on quartiles of average SBP, DBP, PP, and MAP. In men <60 years, average SBP, DBP, and MAP all had strong associations with CVD risk. Men in the highest versus lowest quartiles of average SBP (≥130 versus <116 mm Hg), DBP (≥81 versus <73 mm Hg), and MAP (≥97 versus <88 mm Hg) had RRs of CVD of 2.16, 2.23, and 2.52, respectively. An increased risk of CVD was evident in men aged <60 years in the second quartile of SBP, DBP, and MAP. In men aged ≥60 years, increasing quartiles of SBP and PP were strongly associated with the risk of CVD. Comparing the highest versus lowest quartiles of average SBP (≥135 versus <120 mm Hg) and PP (≥55 versus <44 mm Hg), the corresponding RRs were 1.69 and 1.83. MAP was also associated with the risk of CVD, but with RRs of lower magnitude.

Finally, we examined the joint effect of average SBP and DBP with the CVD risk in men aged <60 and ≥60 years after adjustment for coronary risk factors. In men aged <60 years, single category increases in average SBP (from <120 to the category 120 to <130 mm Hg) or DBP (from <70 to the category 70 to <80 mm Hg) resulted in a 2- or 3-fold increase in CVD risk. In men aged ≥60 years, there were similar patterns of an increased CVD risk but of a lower magnitude. Older men with greater PPs (average SBP 130 to <140 and DBP <70 mm Hg) had the highest RR of CVD.

In sensitivity analyses, we also considered age stratified into 4 age groups (<50, 50 to 59, 60 to 69, and ≥70 years) and compared the age-specific, multivariate RRs of CVD for 10-mm Hg increases in individual blood pressure measures (Figure ). There was a pattern of declining RRs with age for average SBP, DBP, and MAP but not for average PP. These results were further supported by significant interactions found between categories of age and either SBP (P=0.004), DBP (P=0.013), or MAP (P=0.01). The largest reductions in effect sizes with age were for average DBP and MAP, which primarily occurred from ages 50 to 59 to 60 to 69 years. Among other subanalyses, the association between blood pressure and stroke (205 cases) yielded RRs similar to those for CVD, although the smaller number of strokes greatly diminished power. We then considered the associations between blood pressure measures and CVD among men with any past or present history of antihypertensive treatment at baseline. The RRs of CVD for 10-mm Hg increases in SBP (men <60 years, 1.18 men ≥60 years, 1.28), DBP (men <60 years, 1.12 men ≥60 years, 1.24), PP (men <60 years, 1.19 men ≥60 years, 1.20), and MAP (men <60 years, 1.21 men ≥60 years, 1.44) were somewhat different than the results in Tables 2 and 3 .

Discussion

We found modest differences according to age for the relationship between blood pressure and CVD risk in men with no history of antihypertensive treatment after comparing models with 4 different blood pressure measures. Average SBP, DBP, and MAP were all strongly associated with an increased CVD risk in younger men. However, average DBP was not associated with CVD risk in men aged ≥60 years. Average PP was associated with the risk of CVD in both younger and older men.

This study of middle-aged and older men was sufficiently powered to examine the association between various blood pressure measures and risk of CVD. Because we excluded men with any history of antihypertensive treatment, these male physicians had a lower distribution of blood pressure values compared with other community-based cohorts. 5 22 Still, in men aged <60 years, we found an increased CVD risk among men starting in the second quartile of average SBP (≥116 mm Hg), DBP (≥73 mm Hg), and MAP (≥88 mm Hg). In addition to average SBP, PP emerged with a strong positive association with the risk of CVD in men aged ≥60 years. Despite somewhat lower but elevated RRs in men aged ≥60 years, their greater incidence of CVD underscores the potentially large public health impact of elevated yet untreated blood pressure in the elderly.

When we considered SBP and DBP simultaneously, only SBP remained significant in multivariate models for men aged <60 and ≥60 years. During the seventh decade of life, age-specific SBP levels continue to increase, while DBP levels begin to decline. 5 7 8 9 10 We found no independent association between average DBP and CVD risk in men aged ≥60 years. This loss of predictive value for average DBP may be due to an increasing number of men with underlying illnesses 23 however, we would have expected fewer such men in our cohort of apparently healthy male physicians. Isolated systolic hypertension becomes more prevalent with age and has been associated with a significant, increased risk of CVD. 21 24

Increases in PP are associated with aging, particularly after age 60 years. 5 10 Higher levels of PP have been associated with carotid stenosis, 15 left ventricular hypertrophy, 25 MI, 3 26 27 28 CVD death, 12 29 and congestive heart failure 30 in both normotensive and hypertensive populations. Studies in older men and women have found that PP remains important even after controlling for either SBP or DBP. 11 15 30 Our results for average PP in older, but not younger, men were consistent with these findings.

Few studies have prospectively addressed the effect of MAP in relation to CVD. 12 13 14 28 Dyer et al 13 found that the steady component of blood pressure (highly correlated with MAP) was more strongly associated with CVD risk than PP in 4 Chicago epidemiological studies. Among subjects with a history of MI, one study indicated a significant 12% increase in recurrent MI for each 10-mm Hg increase in MAP. 28 However, MAP was a weaker predictor than PP and was not associated with CVD mortality. We found that MAP may be strongly associated with CVD risk in men aged <60 years, with a RR of CVD for a 10-mm Hg increase in average MAP of 1.48. This RR was greater than a RR of 1.33 for a comparable 10-mm Hg increase among French men aged 40 to 54 years. 12

Any clinical advantage for MAP, which is a function of SBP and DBP, for the evaluation of CVD risk among younger men remains unclear. Models with any 2 blood pressure parameters yielded identical −2 log likelihoods for men <60 and ≥60 years because of the linear relationship between blood pressure variables. In this regard, MAP when used in combination with other blood pressure parameters offers no additional ability to predict the risk of CVD. However, among models with single blood pressure parameters in men aged <60 years, MAP was a slightly stronger predictor of CVD than SBP based on −2 log likelihoods. Therefore, in younger men, either MAP or SBP may best predict the risk of CVD when individual blood pressure parameters are considered.

Biologically, the magnitude of RRs of CVD for average SBP in men aged <60 and ≥60 years reflects the strength of its continuous, graded relationship with CVD risk. 1 Higher SBP levels may reflect the progressive stiffening of the arterial wall, changes in the vascular structure, and the development of atherosclerosis. 31 Decreased DBP may indicate poor coronary flow reserve and coronary perfusion of the myocardium. 32 Increases in PP reflect the stiffening of the conduit vessels. Such vessel stiffening increases pulse-wave velocity, which ultimately increases systemic load while decreasing coronary perfusion pressure. 28 MAP is the steady flow of blood through the aorta and its arteries and equals the cardiac output multiplied by vascular resistance. 2

Some limitations should also be considered in light of these results. First, our use of self-reported blood pressure may be subject to misclassification. For example, the weak association between DBP and CVD in men aged ≥60 years may be explained by an underreporting of DBP due to individual differences in recording fourth or fifth Korotkoff sounds. By averaging self-reported blood pressure on the baseline and 2-year questionnaires, we sought to further minimize any misclassification. We excluded men with any history of antihypertensive treatment to reduce any potential confounding by antihypertensive treatment on blood pressure values, although data from Framingham suggest that antihypertensive treatment may not confound the association between blood pressure and coronary heart disease. 11 Next, our findings may not apply to women, lower socioeconomic groups, and non-white populations, who may be more or less susceptible to hypertension and responsive to changes in blood pressure. Finally, unaccounted biochemical, clinical, and genetic markers for the risk of CVD may introduce residual confounding.

In conclusion, among men with no history of antihypertensive treatment, SBP may be best utilized in men aged <60 years, whereas either SBP or PP may be best suited for men aged ≥60 years. DBP was a strong predictor of CVD in younger, but not older, men. Finally, more research must distinguish whether MAP, which is highly correlated with either SBP or DBP, may be an important predictor of CVD in younger men.

Reprint requests to Howard D. Sesso, ScD, MPH, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston MA 02215-1204.

Figure 1. Age-specific RRs and 95% CIs of cardiovascular disease for 10-mm Hg increases in individual average blood pressure parameters. RRs were adjusted for age, body mass index, randomized aspirin treatment, randomized β-carotene treatment, smoking status, vigorous exercise ≥1/wk, alcohol consumption, parental history of MI at <60 years, and history of diabetes.

Table 1. Summary of Self-Reported Coronary Risk Factors According to Age (<60 and ≥60 Years)

Values are mean±SD unless indicated otherwise.

1 Average of self-reported values on the baseline and 2-year follow-up questionnaires.

Table 2. Comparison of RRs (95% CIs) From Cox Proportional Hazards Models 1 of Cardiovascular Disease Among Men Aged <60 Years

1 Models additionally adjusted for age, body mass index, randomized aspirin treatment, randomized β-carotene treatment, smoking status, vigorous exercise ≥1/wk, alcohol consumption, parental history of MI at <60 years, and history of diabetes. These variables contributed 12 more df into each model.

Table 3. Comparison of RRs (95% CIs) From Cox Proportional Hazards Models 1 of Cardiovascular Disease Among Men Aged ≥60 Years

1 Models additionally adjusted for age, body mass index, randomized aspirin treatment, randomized β-carotene treatment, smoking status, vigorous exercise ≥1/wk, alcohol consumption, parental history of MI at <60 years, and history of diabetes. These variables contributed 12 more df into each model.

Table 4. Multivariate 1 RRs (95% CIs) of Cardiovascular Disease According to Approximate Quartiles of Average Blood Pressure, Stratified by Age

1 Adjusted for age, body mass index, randomized aspirin treatment, randomized β-carotene treatment, smoking status, vigorous exercise ≥1/wk, alcohol consumption, parental history of MI at <60 years, and history of diabetes.

2 RR comparing men at or above the 95th percentile vs men in quartile 1.

3 Test for linear trend across quartiles of blood pressure.

This research was supported by research grants CA-40360, CA-34944, HL-26490, and HL-34595 institutional training grant HL-07575 from the National Institutes of Health and a grant from Bristol-Myers Squibb.


Why does systolic blood pressure increases and diastolic bp decrease during exercise?

This is from my 2nd year PBL notes so don't take it as dogma, but it is what I gathered at the time using two physiology textbooks (Martini's and Tortora) as well as leaked official PBL facilitators' notes (lol this took me back to the good ol' days!):

Short term CV changes in dynamic exercise (may be different in weightlifting and other static types of exercise)
-CO --> Increases (5 l/min up to 35 l/min) due to increased HR and SV
-SV --> Increases due to increased sympathetic activity to ventricular myocardium as well as increased EDV (preload) due to increased venous return --> both lead to increased force of contraction (Starling&rsquos law)
-HR --> Increases due to increased sympathetic activity to SA node (N.B. this I think is not strictly true even though it was taken from a textbook. I believe the SA node doesn't get a lot of sympathetic innervation so a more accurate way to put it would be "decreased parasympathetic activity" - this is why atropine (anti-muscarinic) is the first drug of choice in supra-nodal bradycardia rather than an adrenergic agonist. Again this is just personal opinion)
-TPR --> Decreases due to vasodilation in muscle arterioles (with concomittant vasoconstriction in visceral organs)
-MABP --> Increases because the increase in CO > the reduction in TPR
-Pulse Pressure --> Increases due to increased SV and velocity of ejection


So basically to directly answer your question, there is an increased in MABP despite peripheral vasodilation because the increases in HR and SV and consequently CO are bigger than the decrease in TPR.
Systolic BP increases due to increased contractility which leads to increased stroke volume and increased ejection velocity.
Diastolic BP decreases due to peripheral vasodilation.

(Original post by The Only Rivo)
This is from my 2nd year PBL notes so don't take it as dogma, but it is what I gathered at the time using two physiology textbooks (Martini's and Tortora) as well as leaked official PBL facilitators' notes (lol this took me back to the good ol' days!):

Short term CV changes in dynamic exercise (may be different in weightlifting and other static types of exercise)
-CO --> Increases (5 l/min up to 35 l/min) due to increased HR and SV
-SV --> Increases due to increased sympathetic activity to ventricular myocardium as well as increased EDV (preload) due to increased venous return --> both lead to increased force of contraction (Starling&rsquos law)
-HR --> Increases due to increased sympathetic activity to SA node (N.B. this I think is not strictly true even though it was taken from a textbook. I believe the SA node doesn't get a lot of sympathetic innervation so a more accurate way to put it would be "decreased parasympathetic activity" - this is why atropine (anti-muscarinic) is the first drug of choice in supra-nodal bradycardia rather than an adrenergic agonist. Again this is just personal opinion)
-TPR --> Decreases due to vasodilation in muscle arterioles (with concomittant vasoconstriction in visceral organs)
-MABP --> Increases because the increase in CO > the reduction in TPR
-Pulse Pressure --> Increases due to increased SV and velocity of ejection


So basically to directly answer your question, there is an increased in MABP despite peripheral vasodilation because the increases in HR and SV and consequently CO are bigger than the decrease in TPR.
Systolic BP increases due to increased contractility which leads to increased stroke volume and increased ejection velocity.
Diastolic BP decreases due to peripheral vasodilation.

Thanks for giving such a detailed reply. It makes a lot of sense.

Just a question though,so does the pressure in the arteries rise due to increase contractility of the heart and increased stroke volume?

(Original post by 1drowssap)
Thanks for giving such a detailed reply. It makes a lot of sense.

Just a question though,so does the pressure in the arteries rise due to increase contractility of the heart and increased stroke volume?

(Original post by carcinoma)
Yes, MABP=CO*TPR

(Original post by The Only Rivo)
This is from my 2nd year PBL notes so don't take it as dogma, but it is what I gathered at the time using two physiology textbooks (Martini's and Tortora) as well as leaked official PBL facilitators' notes (lol this took me back to the good ol' days!):

Short term CV changes in dynamic exercise (may be different in weightlifting and other static types of exercise)
-CO --> Increases (5 l/min up to 35 l/min) due to increased HR and SV
-SV --> Increases due to increased sympathetic activity to ventricular myocardium as well as increased EDV (preload) due to increased venous return --> both lead to increased force of contraction (Starling&rsquos law)
-HR --> Increases due to increased sympathetic activity to SA node (N.B. this I think is not strictly true even though it was taken from a textbook. I believe the SA node doesn't get a lot of sympathetic innervation so a more accurate way to put it would be "decreased parasympathetic activity" - this is why atropine (anti-muscarinic) is the first drug of choice in supra-nodal bradycardia rather than an adrenergic agonist. Again this is just personal opinion)
-TPR--> Decreases due to vasodilation in muscle arterioles (with concomittant vasoconstriction in visceral organs)
-MABP --> Increases because the increase in CO > the reduction in TPR
-Pulse Pressure --> Increases due to increased SV and velocity of ejection


So basically to directly answer your question, there is an increased in MABP despite peripheral vasodilation because the increases in HR and SV and consequently CO are bigger than the decrease in TPR.
Systolic BP increases due to increased contractility which leads to increased stroke volume and increased ejection velocity.
Diastolic BP decreases due to peripheral vasodilation.

Sports science intercalatee here! This is roughly my understanding as well: my only caveats would be that the response varies with exercise type and intensity (and also to say weightlifting, bodyweight movements, etc. are all still forms of dynamic exercise!).

For HR: Initially (before exercise starts): increased SNS activity with reciprocal decreased PSNS activity. As exercise starts, most change is due to further PSNS withdrawal (like you said): but the more intense you get, the more SNS contribution there is. Feedback from peripheries (how much blood how much o2 what pH etc.) also ends up playing an indirect role.

Increased skeletal muscle pump action contributes to the increased MAP in exercise, also.

Systolic shoots up as soon as you start exercise, then slowly increases with exercise intensity (this is mostly the CO). Diastolic has no big drop, but again, only slowly decreases with increased intensity (would drop due to vasodilation, but is counterbalanced by the CO: hence why you can see no change to a small change, vs the big changes in systolic). For exercise intensities you could keep up for a long time (like in a 10K), there's not usually a change on DBP.

The weightlifting response is totally different: concentric contraction compresses arteries -> "I'm not getting blood. " response -> huge spike in CO & MAP. Both SBP and DBP increase a large amount here. More intense the lift, the bigger the jump.

Afrerload is the TPR as far as we're concerned, really. For moderate exercise, afterload decrease contributes to increased CO. In things like weightlifting, afterload is increased, but there's an increased drive (beat harder) and you get increased CO anyway (this is likely why weightlifter's hearts undergo a different type of hypertrophy from endurance athlete's hearts).


How One Can Lower Systolic Pressure without Lowering Diastolic Pressure

How One Can Lower Systolic Pressure without Lowering Diastolic Pressure

Blood pressure is measured in two numbers the systolic and the diastolic. Systolic number is the reading of the pressure exerted on the walls of your blood vessels when the heart is pumping. Diastolic reading is the pressure of the blood on the artery walls when the heart is between beats. People whose blood pressure is high will usually have high levels of both systolic and diastolic. However, there are some cases where a person has a high systolic level but a normal or low diastolic level. This condition is called isolated systolic hypertension and is treated by lowering the systolic without further decreasing diastolic level.

Determining the cause of isolated systolic hypertension is crucial before any dietary changes or exercise is recommended. Hence, get a thorough check up from a medical specialist. Its underlying causes may be a leaky heart valve or an overactive thyroid gland.

If your systolic hypertension is not caused by any heart condition, you can exercise to get your heart in a good condition. A stronger heart can pump more blood with less force, thus lowering the systolic level. Moderate to vigorous exercise of 30 minutes at least five times a week is recommended by the American Heart Association for a fit heart.

Your doctor can also prescribe special medicines that work at lowering systolic level without affecting the diastolic if your heart is not strong enough to perform cardio activity. Thiazide diuretics, for example Saluron and Trichlorex, and calcium antagonists such as Norvasc and Procardia are two of the best classes of drugs used for this purpose. These drugs were also recommended by a 2001 study published in Nephrology Dialysis Transplantation. Drugs that strengthen the heart, like Digitalis, are also beneficial in isolated systolic hypertension. Such drugs toughen the heart contractions and allow the heart to exert less force to pump the same amount of blood, therefore, decreasing systolic pressure.

In order to bring your systolic blood pressure with in normal range, it is also necessary to reduce stress from your life. Your blood vessels become tensed when you are anxious, worried or irritated by something. You will know about the things that relax you. Try doing them when you are worried or tensed whether it is listening to music or taking a walk in the garden. When your body is relaxed and at peace, you blood pressure will also return to normal.

Exercise and relaxation techniques will not lower your systolic blood pressure if your diet is not changed accordingly. Base you diet on the DASH (Dietary Approaches to Stop Hypertension). This approach is based on studies done at the National Heart, Lung and Blood Institute. According to DASH, your meals should be low in sodium because it causes the body to retain fluid and makes the kidneys work harder. Resultantly, blood has more volume and the heart is forced to pump harder.

Furthermore, people who are trying to lower their systolic pressure should eat food that is rich in potassium, magnesium and calcium as these are good for maintaining blood pressure and prevent cholesterol build up in the arteries. Eat lots of fruit and vegetable, whole grains, poultry and fish. Stay away from fatty foods as these are not healthy for blood pressure levels.