Physical Exercise, Inflammation, And Hypertension: How To Improve Cardiovascular Prevention

This Focus Issue on epidemiology, prevention, and healthcare policies contains the Special Article ‘Sex differences in arterial hypertension: a scientific statement from the ESC Council on Hypertension, the European Association of Preventive Cardiology, Association of Cardiovascular Nursing and Allied Professions, the ESC Council for Cardiology Practice, and the ESC Working Group on Cardiovascular Pharmacotherapy’ by Eva Gerdts from the University of Bergen in Norway, and colleagues.¹ It is well recognized that hypertension is a potent risk factors for both men and women.^2–7 The authors note, however, that there is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV) risk factors, and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease (CVD) increases at a lower BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to a paucity of data, particularly from specifically designed clinical trials, it is not yet known whether hypertension should be managed differently in females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was conceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over the life course, pathophysiological mechanisms regulating BP, interaction of BP with CV risk factors and co-morbidities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CVD, and differences in the effect of antihypertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and management of hypertension.

Figure 1

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Structured Graphical Abstract.⁸

The interplay between the volume and intensity of physical activity is poorly understood in relation to CVD risk. In a Clinical Research article entitled ‘Physical activity volume, intensity and incident cardiovascular disease’, Paddy Dempsey from the University of Leicester in the UK, and colleagues aimed to investigate the role of physical activity intensity, over and above volume, in relation to incident CVD.⁸ Data were from 88 412 UK Biobank middle-aged adults (58% women) without prevalent CVD who wore accelerometers on their dominant wrist for 7 days, from which the authors estimated total physical activity energy expenditure (PAEE) using population-specific validation. Cox proportional hazards regressions modelled associations between PAEE (kJ/kg/day) and physical activity intensity (%MVPA; the fraction of PAEE accumulated from moderate to vigorous intensity physical activity) with incident CVD (ischaemic heart disease or cerebrovascular disease), adjusted for potential confounders. There were 4068 CVD events during 584 568 person-years of follow-up (median 6.8 years). Higher PAEE and higher %MVPA (adjusted for PAEE) were associated with lower rates of incident CVD. In interaction analyses, CVD rates were 14% lower when %MVPA accounted for 20% rather than 10% of 15 kJ/kg/d PAEE; equivalent to converting a 14 min stroll into a brisk 7 min walk. CVD rates did not differ significantly between values of PAEE when the %MVPA was fixed at 10%. However, the lowest CVD rates were observed for combinations of both higher PAEE and %MVPA (Figure 1).

The authors conclude that reductions in CVD risk may be achievable through higher physical activity volume and intensity, with the role of moderately intense physical activity appearing particularly important. This supports multiple approaches to or strategies for physical activity participation, some of which may be more practical or appealing to different individuals.

Physical exercise is associated with a reduced CV risk.^9–12 Vigorous physical activity (VPA) is a time-efficient way to achieve recommended physical activity levels. In a Clinical Research article entitled ‘Vigorous physical activity, incident heart disease, and cancer: how little is enough?’, Matthew Ahmadi from the University of Sydney, NSW in Australia, and colleagues note that there is a very limited understanding of the minimal and optimal amounts of VPA in relation to mortality and disease incidence.¹³ In a prospective study in 71 893 adults (median age 62.5 years, 56% female) from the UK Biobank cohort with wrist-worn accelerometry, VPA volume (min/week) and frequency of short VPA bouts (≤2 min) were measured. During a mean post-landmark point follow-up of 5.9 years, the adjusted 5-year absolute mortality risk was 4.17% for no VPA, 2.12% for >0 to <10 min, 1.78% for 10 to <30 min, 1.47% for 30 to <60 min, and 1.10% for ≥60 min/week. The ‘optimal dose’ (nadir of the curve) was 53.6 min/week [hazard ratio (HR) 0.64] relative to the fifth percentile reference (2.2 min/week). There was an inverse linear dose–response association of VPA with CVD mortality. The ‘minimal’ volume dose was ∼15 min/week for all-cause (HR 0.82) and cancer (HR 0.84) mortality, and 19.2 min/week (HR 0.60) for CVD mortality. These associations were consistent for CVD and cancer incidence.

Ahmadi et al. conclude that VPA of 15–20 min/week was associated with a 16–40% lower mortality, with further decreases up to 50–57 min/week. These findings suggest reduced health risks may be attainable through relatively modest amounts of VPA accrued in short bouts across the week.

The two contributions by Dempsey and Ahmadi are accompanied by a Double Editorial by Charles Matthews and Pedro Saint-Maurice from the United States National Cancer Institute in Bethesda, MD, USA.¹⁴ The authors note that current physical activity recommendations are predicated on the idea that both the hare and the tortoise can win the race for better health, but the provocative studies detailed above give an edge to the hare’s higher intensity approach. Future studies are needed to examine the consistency of these new findings in other study populations and/or using a range of analytical methods and employing rigorously developed and validated accelerometer-based prediction algorithms. These will be the critical next steps to build upon the current findings, and hopefully avoid unexpected findings in our race to find a variety of strategies to increase physical activity and prevent CVD and cancer.

Figure 2

The Swedish Cardiopulmonary Resuscitation Registry was used to study 30-year trends in out-of-hospital cardiac arrest (OHCA) and 17-year trends in in-hospital cardiac arrest (IHCA). A total of 106 296 cases of OHCA (1990–2020) and 30 032 cases of IHCA (2004–2020), in whom resuscitation was attempted, were studied. Trends in 30-day survival, cerebral performance category among survivors, causes of cardiac arrest, initial rhythm, critical time intervals, and bystander cardiopulmonary resuscitation (CPR) were studied.¹⁹

Survival after cardiac arrest remains a challenging therapeutic goal.^15–18 In a Clinical Research article entitled ‘Trends in survival after cardiac arrest: a Swedish nationwide study over 30 years’, Matilda Jerkeman from the University of Gothenburg in Sweden, and colleagues assessed trends in characteristics, management, and survival in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) in the Swedish Cardiopulmonary Resuscitation Registry (SCRR).¹⁹ The SCRR was used to study 106 296 cases of OHCA (1990–2020) and 30 032 cases of IHCA (2004–2020) in whom resuscitation was attempted. In OHCA, survival significantly increased from 5.7% in 1990 to 10.1% in 2011, and remained unchanged thereafter. Survival increased for all aetiologies, except trauma, suffocation, and drowning. Bystander cardiopulmonary resuscitation increased from 31% to 82%. Shockable rhythm decreased from 39% in 1990 to 17% in 2020. In IHCA, the odds ratio (OR) for survival in 2017–2020 vs. 2004–2007 was 1.18, significant but not large, showing, however, a non-linear trend, with probability of survival increasing by 47% during 2011–2020. Myocardial ischaemia or infarction as aetiology significantly decreased during 2004–2020 from 67% to 28%. Shockable rhythm significantly decreased from 37% to 23%. Approximately 90% of survivors (IHCA and OHCA) had no or mild neurological sequelae (Figure 2).

Jerkeman et al. conclude that survival increased 2.2-fold in OHCA during 1990–2020 but without any improvement in the final decade, and 1.2-fold in IHCA during 2004–2020, with rapid improvement in the last decade. This manuscript is accompanied by an Editorial by Elizabeth Paratz and André La Gerche from the Baker Heart and Diabetes Institute in Melbourne, Australia.²⁰ The authors highlight that the strength of the data of Jerkeman et al. is that the relatively large population and consistent definitions enable an excellent snapshot of the trends in cardiac arrest science. They propose a range of ambitious initiatives to drive future improvement in arrest survival: wearable technology arrest alerts, mobile phone-initiated recruitment of bystanders, drone-mediated delivery of defibrillators, ‘in-the-field’ extracorporeal membrane oxygenation, and geolocation assistance to reduce ambulance times. They conclude that the Swedish collaborative registry deserves praise. High-quality clinical registries such as the SCRR enable us to monitor the incremental real-time benefit of each innovation. Informed and systematic implementation of many small steps should enable us to favourably disrupt the current plateau in cardiac arrest survival.

Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease.^21–25 Yet, after the initiation of statin therapy, the relative contributions of these processes may differ in patient groups, such as those with and without impaired kidney function. Paul Ridker from Brigham and Women’s Hospital in Boston, MA, USA and colleagues investigate this in a Clinical Research article entitled ‘Inflammation drives residual risk in chronic kidney disease: a CANTOS substudy’.²⁶ Among 9151 stable statin-treated post-myocardial infarction patients participating in the CANTOS trial, the contributions of residual cholesterol risk and residual inflammatory risk were evaluated as determinants of recurrent major adverse cardiovascular events (MACE) and total mortality, stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.73 m² using the race agnostic CKD-EPI 2021 formula (all participants had eGFR >30 mL/min/1.73 m²). Analyses of residual inflammatory risk focused on high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), while analyses of residual cholesterol risk focused on LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C). Participants were followed for a period of up to 5 years (median 3.7 years). Among participants with eGFR ≥60 mL/min/1.73 m², increasing quartiles of plasma hsCRP, IL-6, LDL-C, and non-HDL-C were all positively associated with risks of recurrent MACE (HR comparing the top with the bottom quartile for hsCRP 1.45; for IL-6 2.48; for LDL-C 1.64; and for non-HDL-C 1.68, all P <0.0001). In contrast, among those with eGFR <60 mL/min/1.73 m², increasing quartiles of hsCRP and IL-6 significantly predicted recurrent MACE (HR comparing the top with the bottom quartile for hsCRP 1.50, P = 0.021; for IL-6 1.84, P = 0.048), whereas increasing quartiles of LDL-C and non-HDL-C did not. The predictive utility of hsCRP and IL-6 in the setting of eGFR <60 mL/min/1.73 m² remained significant after adjustment for a wide range of potential confounding factors including age, sex, smoking status, BP, body mass index, and diabetes. For the endpoint of total mortality, both hsCRP (HR 1.77, P = 0.0021) and IL-6 (HR 2.15, P = 0.015) were significant predictors among those with eGFR <60 mL/min/1.73 m², whereas LDL-C and non-HDL-C were not. Similar effects were observed in analyses stratified by the albumin to creatinine ratio rather than eGFR.

The authors conclude that among post-myocardial infarction patients with impaired kidney function already aggressively treated with statin therapy, residual inflammatory risk plays a substantial role in determining the risk of recurrent CV events. These data have implications for risk stratification of individuals with chronic kidney disease and for the development of novel agents that target inflammatory processes in this high-risk group of patients. The manuscript is accompanied by an Editorial by Stefan Mark Nidorf from the Harry Perkins Institute of Medical Research in Perth, WA, Australia.²⁷ Nidorf notes that there is an urgent need to develop agents that effectively target crystal-induced inflammation to reduce the inflammatory risk in patients cholesterol intolerant to colchicine, and are safe in CKD. The ZEUS trial (NCT05021835), designed to meet this challenge, will examine the effects of blocking IL-6 with ziltivekimab in patients with CKD and an hsCRP ≥2. To date, preliminary data look promising. Ziltivekimab appears safe in advanced CKD; lowers hsCRP more than canakinumab; lowers IL-6 more than methotrexate; and, unlike canakinumab and other monoclonal antibodies that target IL-6, does not appear to increase the risk of infection nor does it increase LDL levels. In large part, ZEUS is a continuum of the impressive and relentless efforts of the CANTOS investigators to focus attention on the role of inflammation in atherosclerosis, in the pursuit of safe and effective therapies to reduce inflammatory risk in patients with coronary disease. Should ZEUS ‘reign over the spectre of inflammation’ and improve clinical outcomes in CKD, it will be a major advance in the treatment of atherosclerosis.

The issue is complemented by two Discussion Forum contributions: in a contribution entitled ‘Adding salt at the table: a marker of an unhealthy diet’, Franz H. Messerli from the University Hospital of Bern in Switzerland, and colleagues comment on the recent publication ‘Adding salt to foods and hazard of premature mortality’ by Lu Qi from Tulane University in New Orleans, LA, USA.^28,29 Qi et al. respond in a separate comment.³⁰

The editors hope that this issue of the European Heart Journal will be of interest to its readers.

Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.