According to the lead author of the study, Prof Paola Palatini of the University of Padova (Italy), the findings of their study may warrant starting BP-lowering treatment - including pharmacotherapy - earlier in patients with an exaggerated BP response upon standing.²

Prevalence of hypertension

About 40% of people worldwide have hypertension, considered to be the world's leading preventable cause of death.² In South Africa, hypertension is one of the most common non-communicable diseases.³

The 2012 South African National Health and Nutrition Examination Survey, found that almost 30% of South Africans ≥ 15 years have hypertension.⁴ The 2016 South African Demographic Health Survey indicated a hypertension prevalence in females at 46% and 44% in males.⁵

Over the last few decades, the prevalence of hypertension has increased substantially in South Africa across all race groups. This is mainly a result of urbanisation, and associated behavioural risk factors such as poor diet, physical inactivity, alcohol and tobacco use, as well as stress.^4,6

Apart from CV events, people with hypertension in mid-life are five times more likely to have impaired cognitive function and twice as likely to experience reduced executive function, dementia, and Alzheimer's disease.²

What did the AHA study find?

Typically, systolic BP (SBP) falls slightly upon standing. In this study, researchers assessed whether the opposite response - a significant rise in SBP upon standing - is a risk factor for MI and other serious CV events.²

The investigators evaluated participants (n=1207) who were part of the Hypertension and Ambulatory Recording Venetia or HARVEST study, which was started in Italy in 1990 and included adults ages 18- to 45 years with untreated stage 1 hypertension.²

Stage 1 hypertension was defined as SBP of 140mmgHg-159mmHg and/or diastolic BP (DBP) 90mmHg-100mmHg. None had taken BP-lowering medication prior to the study, and all were initially estimated at low risk for major CV events based on their lifestyle and medical history (no diabetes, renal impairment, or other CVDs). At enrolment, participants were an average age of 33 years and 72% were men.²

At enrolment, six BP measurements for each participant were taken in various physical positions, including when lying down and after standing up. The 120 participants with the highest increase (top 10%) in BP upon standing averaged an 11.4mmHg increase. The remaining participants averaged a 3.8mmHg fall in SBP when standing up.²

The researchers compared CVD risk factors, laboratory measures and the occurrence of major CV events (MI, heart-related chest pain, stroke, aneurysm of the aortic artery, clogged peripheral arteries) and chronic kidney disease among participants in the two groups.²

In some analyses, the development of AFib, a major risk factor for stroke, was also noted. Results were adjusted for age, gender, parental history of heart disease, and several lifestyle factors and measurements taken during study enrolment. During an average 17-year follow-up, 105 major CV events occurred. The most common were MI, heart-related chest pain and stroke.²

Participants in the group with a top 10% rise in BP:²

• Were almost twice as likely as other participants to experience a major CV event
• Did not generally have a higher risk profile for CV events during their initial evaluation (outside of the exaggerated BP response to standing)
• Were more likely to be smokers (32.1% vs. 19.9% in the non-rising group), yet physical activity levels were comparable, and they were not more likely to be overweight or obese, and no more likely to have a family history of CV events
• Had more favourable cholesterol levels (lower total cholesterol and higher high-density-lipoprotein cholesterol)
• Had lower SBP when lying down than the other group (140.5mmHg vs 146mmHg, respectively), yet BP measures were higher when taken over 24 hours.

After adjusting for average BP taken over 24 hours, an exaggerated BP response to standing remained an independent predictor of adverse CV events or stroke.²

According to Prof Palatini, the results of the study confirmed their initial hypothesis - a pronounced increase in BP from lying to standing could be prognostically important in young people with hypertension.²

“We were rather surprised that even a relatively small increase in standing BP (6mmHg-7mmHg) was predictive of major CV events in the long run," he added.²

In a subset of 630 participants who had stress hormones measured from 24-hour urine samples, the epinephrine/creatinine ratio was higher in the people with a rise in standing BP compared to those whose standing BP did not rise (118.4nmol/mol vs 77nmol/mol, respectively).²

Epinephrine levels are an estimate of the global effect of stressful stimuli over the 24-hours. This suggests that those with the highest BP when standing may have an increased fight-or-flight response to stressors, which causes an increase in average BP.²

The findings suggest that BP upon standing should be measured in order to tailor treatment for patients with hypertension, and potentially, a more aggressive approach to lifestyle changes and BP-lowering therapy may be considered for people with an elevated BP response to standing.²

The authors did caution that the results from this study may not be generalisable to people from other ethnic or racial groups since all study participants reported white race/ethnicity. In addition, there were not enough women in the sample to analyse whether the association between rising standing BP and adverse CV events was different among men and women.²

Stress as a potentially modifiable risk factor for CVD

The fight-or-flight reaction is an automated brain response when we are in a stressful situation. As shown by Palatini et al, this response is increased in patients with high BP levels and as mentioned above, hypertension is the leading cause of CVD. So can managing this stress response prevent the development and progression of CVD? ^2,7

According to Vancheri et al, the role of mental stress - defined as a negative cognitive and emotional body response to environmental demands that exceed an individual’s ability to cope - is increasingly being recognised as a potential modifiable risk factor of CVD, independent of conventional risk factors.⁷

Stress can cause increased oxygen demand on the body, spasm of the coronary blood vessels, and electrical instability in the heart's conduction system. Stress has been shown to increase the heart rate and BP, making the heart work harder to produce the blood flow needed for bodily functions.^7,8

Stress can be either acute or chronic. Acute stress is short-term exposure to severe stressors, while chronic stress refers to long-term, repetitive exposure to stressors.

Stressors are real or perceived threats. The brain evaluates and appraises these threats and ‘ranks’ them based on previous and current experiences.⁷

Acute stress can be experienced daily as the result of anger, fear, acute job-strain, or stressful sport events, as well as during natural disasters, earthquakes, and hurricanes, or unnatural events including industrial accidents and terrorist attacks.⁷

Significant acute stress may trigger angina, myocardial infarction, arrhythmias, stress cardiomyopathy (Takotsubo syndrome), stroke, or sudden death. The risk of acute coronary syndromes has been estimated to be five times higher in the second after an anger outburst.⁷

Chronic stress may be caused by depression, anxiety, low self-esteem, loneliness, job-related stress, retirement, low socioeconomic status, and type A personality (eg competitive, aggressive, hostile) and type D (eg distressed, characterised by introversion and pessimistic emotions).⁷

Studies show that on average, work-related chronic stress is associated with a 50% excess risk of CVD. Moreover, long-term exposure to stress has been linked to the development of diabetes and obesity, which greatly increase CVD risk.⁷

Although stress is a common experience in daily life, some people experience pathological CV consequences, particularly those with significant CVD risks, stress Vancheri et al.⁷

The risk of a CV event brought on by mental stress depends on a combination of external events and an individual’s threshold for experiencing stress. The latter is influenced by genetics and early and adult life experiences, which accounts for the differences in how people respond to stressors.⁷

Managing risk factors to reduce CVD events

As mentioned above, hypertension is the leading cause of CVD. The risk of CVD rises with increasing BP levels. Studies, including several hundred thousand patients, have shown that a 10mmHg reduction in SBP or a 5mmHg reduction in DBP is associated with significant reductions in all major CV events (∼20%), all-cause mortality (10%-15%), stroke (∼35%), coronary events by (∼20%), and heart failure (∼40%).⁹

These relative risk reductions are consistent, irrespective of baseline BP within the hypertensive range, the level of CV risk, comorbidities (eg diabetes and chronic kidney disease), age, sex, and ethnicity.⁹

According to the AHA and the American College of Cardiology (ACC), hypertension increases the risk for progression to more severe hypertension as well as risk for CV events and mortality. The 2021 AHA/ACC stage 1 and 2 hypertension guidelines recommend (see table 1): ¹⁰

Table: The 2021 AHA/ACA guidelines recommendations¹⁰

Earlier intervention among these patients (see table 1) has the potential to blunt the progression of hypertension and avert CVD complications.¹⁰

According to the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guidelines, the main objective of hypertension management is to reduce BP to <140/90mmHg, with a target of 130/80mmHg or lower, if tolerated, in adults younger than 65 years, but not in adults 65 years and older, for whom the target is below 140mmgHg to 130/80mmHg if tolerated.⁹

The ESC/ESH guidelines stress that patients with grade 2 (160-179mmHg/100-109mmHg) and or 3 hypertension (≥180/110mmHg) should receive immediate antihypertensive drug treatment alongside lifestyle interventions (salt restriction, moderation of alcohol consumption, high consumption of vegetables and fruits, weight reduction and maintaining ideal body weight, regular physical activity, and smoking cessation). In both these patient populations, aim for BP control within three months.⁹

The majority of guidelines recommend five major drug classes as the basis for the treatment of hypertension: angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers, calcium channel blockers (CCBs), and diuretics (thiazides and thiazide-like diuretics such as chlortalidone and indapamide).⁹

However, only about 35% of patients with hypertension are adequately controlled using monotherapy. As a result, guidelines increasingly recommended a stepped-care approach (initiating treatment with different monotherapies and then sequentially adding other drugs until BP control is achieved).⁹

But according to the authors of the ESC/ESH guidelines, this approach has also not improved BP control because of ineffective drug therapy, physician or treatment inertia, patient non-adherence to treatment, insufficient use of combination treatment and the complexity of current treatment strategies.⁹

The ESC/ESH guidelines state that the most effective evidence-based treatment strategy to improve BP control is one that:⁹

• Encourages the use of combination treatment in most patients, especially in the context of lower BP targets
• Enables the use of single-pill combination (SPC) therapy for most patients, to improve adherence to treatment
• Follows a treatment algorithm that is simple, applies to all patients, and is pragmatic, with the use of SPC therapy as initial therapy for most patients, except those with BP in the high–normal range and in frail older patients.

The guidelines recommend the following treatment algorithm:⁹

1. The initiation of treatment in most patients with an SPC comprises two drugs, to improve the speed, efficiency, and predictability of BP control.
2. Preferred two-drug combinations are a RAS blocker (ACEi or ARB) with a CCB or a diuretic. A beta-blocker in combination with a diuretic or any drug from the other major classes is an alternative when there is a specific indication for a beta-blocker eg angina, post-MI, heart failure, or heart rate control.
3. Use monotherapy for low-risk patients with stage 1 hypertension whose SBP is <150mmHg, very high-risk patients with high–normal BP, or frail older patients.
4. The use of a three-drug SPC comprising a RAS blocker, a CCB, and a diuretic if BP is not controlled by a two-drug SPC.
5. The addition of spironolactone for the treatment of resistant hypertension, unless contraindicated.
6. The use of other classes of antihypertensive drugs in rare circumstances in which BP is not controlled by the above treatments.

Managing the mind-heart-body connection

As mentioned above, stress is increasingly being recognised as a potentially modifiable risk factor of CVD, independent of conventional risk factors. In a scientific statement, the AHA (2021) cautions that clinicians should strive to treat not just the disease state but the patient and the person as a whole and emphasises that the psychological health of a person (a person’s mind) can positively or negatively affect his/her CV health, CV risk factors, the risk for CVD events, and CV prognosis over time. This intertwined relationship is referred to as the mind-heart-body connection.^7,11

The AHA recommends positive psychology and stress management programmes for patients with CVD. Studies have found that a number of positive psychological attributes (eg optimism, sense of purpose, gratitude, mindfulness) are associated with a lower risk of CVD and mortality.¹¹

The AHA recommends the following to improve the psychological health of patients with CVD:¹¹

• Consideration of psychological health is advisable in the evaluation and management of patients with or at risk for CVD
• Simple screening measures can be used by healthcare professionals for patients with or at risk for CVD to assess psychological health status
• Interventions to improve psychological health such as psychotherapy (eg positive psychology programmes using systematic activities [eg personal strengths, recalling positive life events] to improve psychological attributes and experiences [optimism, positive affect], or stress management (eg meditation training and mindfulness-based interventions) have been shown to improve CV health.

References

1. Kjeldsen SE. Hypertension and cardiovascular risk: General aspects. Pharmacol Res, 2018.
2. Palatini P, Mos L, Saladini F, Rattazzi M. Blood Pressure Hyperreactivity to Standing: a Predictor of Adverse Outcome in Young Hypertensive Patients. Hypertension, 2022.
3. Bradshaw D, Nannan N, Groenewald P, et al. Provincial mortality in South Africa, 2000: priority-setting for now and a benchmark for the future. South Afr. Med, J, 2005.
4. Shisana O, Labadarios D, Rehle T, et al. South African National Health and Nutrition Examination Survey (SANHANES-1) HSRC Press; Cape Town, South Africa: 2014.
5. National Department of Health (NDoH) Statistics South Africa (Stats SA) South African Medical Research Council (SAMRC) ICF. South Africa Demographic and Health Survey 2016: Key Indicator Report, 2017.
6. Adeloye D, Basquill C. Estimating the Prevalence and Awareness Rates of Hypertension in Africa: A Systematic Analysis. PLoS ONE. 2014
7. Vancheri F, Longo G, Vancheri E, Henein MY. Mental Stress and Cardiovascular Health-Part I. J Clin Med, 2022.
8. Torpy JM. Chronic Stress and the Heart. JAMA, 2007.
9. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). European Heart Journal, 2018.
10. Goetsch MR, Tumarkin E, Blumental RS, Whelton S. New Guidance on Blood Pressure Management in Low-Risk Adults with Stage 1 Hypertension. https://www.acc.org/latest-in-cardiology/articles/2021/06/21/13/05/new-guidance-on-bp-management-in-low-risk-adults-with-stage-1-htn
11. Levine GN, Cohen BE, Commodore-Mensah Y, et al. Psychological Health, Well-Being, and the Mind-Heart-Body Connection: A Scientific Statement From the American Heart Association. Circulation, 2021.