SCIENTIFIC JOURNAL of the Hungarian Society of Cardiology

The year in cardiovascular medicine 2020: epidemiology and prevention

█ Current opinion

Ramon Estruch1,2 Luis M Ruilope3,4,5 Francesco Cosentino6
1Department of Internal Medicine, Hospital Clínic, IDIBAPS, University of Barcelona, Villarroel, 170. 08036 Barcelona, Spain;
2CIBER Fisiopatología de la Obesidad y la Nutrición, CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain;
3Hypertension Unit and Cardiorenal Translational Laboratory, Research Institute, Hospital Universitario, 12 de Octubre, Madrid, Spain;
4CIBER Enfermedades Cardiovasculares, CIBER-CV Hospital Universitario, 12 de Octubre, Avd. de Córdoba s/n. 28041 Madrid, Spain;
5Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain;
6Cardiology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, FE 200, 171 77 Stockholm, Sweden


Cardiovascular disease (CVD) prevention has been classically divided into primary (aimed to asymptomatic subjects) and secondary (aimed to patients who have
already suffered a cardiovascular event), but currently this classification is considered arbitrary given the overlap observed, for example in diabetic patients. Thus,
prevention measures may be better divided into “prevention at the population level” and “prevention strategies in subjects with high vascular risk” (1–3). Figure 1 summarizes the role of different actors in the prevention of CVD.


Lifestyle, behaviour, and environmental factors

Both sex and gender have significant impact on the incidence and severity of cardiovascular events (4). Compared to men, women disclose a higher incidence of some cardiovascular conditions such as heart failure with preserved ejection fraction (5) or Takotsubo syndrome (6), but they also suffer from relevant differences in presenting symptoms of acute coronary syndrome (ACS) (7, 8). Perhaps, different treatment protocols should be applied in men and women to avoid the differences observed.
New advances on precision nutrition occur every year. Although the relevance of dietary cholesterol on health has been questioned in the last years (9, 10), Helgadottir et al. (11). have found that sequence variants that decrease the function of ABC5/8 transporters increase the absorption of both dietary cholesterol and phytosterols, thereby increasing the risk of coronary artery disease (CAD).


Smoking and vaping
The use of electronic cigarettes (e-cigarettes) has dramatically increased, especially among young generations. Although e-cigarettes may be useful to save smokers or generate new addicts, the list of toxic compounds found in e-cigarette vapour is large, mainly nicotine, propylene glycol, and glycerine (12). In fact, daily e-cigarette use has been associated with increased CVD morbidity and mortality (12), and various forms of pneumonitis (13). Kuntic et al. (14) demonstrated that the e-cigarette use is associated with a marked impairment in endothelium-dependent flow-mediated vasodilatation and an increase in pulse wave velocity, a measurement of arterial stiffness. They also observed in mice that e-cigarette vapour raised blood pressure (BP) and increased superoxide production that reacts with nitric oxide in peripheral arteries and brain cortex. Thus, e-cigarettes are truly toxics and the recommendation should be to never start their use and for users to stop them (15).

The most important strategy for the prevention of atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and atrial fibrillation (AF) is to promote a healthy lifestyle. Mediterranean diet is considered as one of the most cost-effective strategies to prevent CVD (16), but individual responsiveness to compliance with this dietary pattern may vary due to differences in metabolic responses. Li et al. (17) identified a metabolic signature comprised of 67 metabolites that correlated with the Mediterranean diet adherence screener and also predicted future CVD risk independent of traditional risk factors in a Spanish (PREDIMED) and three US cohorts (NHS, NHSII, and HPFSP). Metabolomics profiling may allow stratifying individuals based on dietary response and disease risk, thus facilitating individualized approaches to dietary interventions.

In addition to CAD, diet may affect stroke risk. Tong et al. (18) examined the association between intake of major foods and fibre with risk of ischaemic and haemorrhagic stroke in 418 329 participants in the EPIC cohort. For ischaemic stroke, participants with high consumption of fruit and vegetables combined, dietary fibre, milk, yogurt, and cheese reduced risks by 13%, 23%, 5%, 9%, and 12%, respectively. Interestingly, for haemorrhagic stroke, higher risk was only associated with higher egg consumption, with a 25% increase per 20 g/day.
Notably, iron overload profoundly aggravated atherosclerotic damage in an APOE-deficient mouse model (19), but iron deficiency was associated with a worse outcome in a cohort of 2357 patients with HF studied by van der Wal et al. (20). Depending on the context, iron excess and iron deficiency may both be harmful to cardiovascular health.
Excessive alcohol intake always affects the cardiovascular system, including induction of AF and adverse atrial remodelling. A randomized clinical trial (RCT) of continuous alcohol drinking vs. abstinence in patients with AF demonstrated reduced arrhythmia rates during a 6-month follow-up in the group assigned to abstinence (21), emphasizing the present recommendation to abstain from alcohol in patients with recurrent AF.

Physical activity is associated with a dose-dependent reduction in all-cause and CVD mortality (22). This assertion was reconfirmed by a very large study of persons with and without CVD (23). Physical activity should be promoted in young ages, since low levels of cardiorespiratory fitness (and obesity) in 1 078 685 male adolescents were associated with later cardiovascular disabilities (24). Physical activity and cardiorespiratory fitness were also associated with lower long-term risk of CVD and all-cause mortality in patients with AF (HUNT study) (25). Likewise, incidence of AF and ventricular arrhythmias was lower among those who were physically active and remained relative stable over a broad range of activity levels (26).
Finally, sport may favour healthy aging (27). In this respect, a controlled trial (EXAMIN AGE) of high-intensity interval training in aged individuals reported restoration of retinal microvascular dysfunction, a clinical outcome associated with major adverse cardiovascular events (MACE), together with the reduction of other cardiovascular risk factors (28, 29).

Association between obesity and all-cause and CVD mortality follows a J-shaped curve (30). Over two-thirds of deaths attributable to high body mass index (BMI) are due to CVD, mainly CAD (31), but the causal role of adiposity for other CVD outcomes remains unclear. In a Mendelian randomization study, Larsson et al. (32) assessed the association of BMI-related genetic variants with 14 cardiovascular conditions among 367 703 UK Biobank participants and reported that higher BMI was associated with increased risk of aortic valve stenosis, AF, ischaemic stroke and abdominal aortic aneurisms.
Among diets used to lose weight (30), intermittent fasting has gained increased popularity since it is purported to not only help reduce body weight, but also to reverse aging, increase lifespan, and improve several other chronic conditions, albeit most evidence is preclinical (33). Concerning weight loss effects, Moussa et al. (34) evaluated the long-term effect of bariatric surgery on CVD outcomes in a UK nationwide nested cohort study. Occurrence of MACE (mainly myocardial infarction) and new HF diagnoses were reduced by nearly 60% in obese individuals who underwent the procedure compared to a matched control group.

Other lifestyle factors
Emerging evidence has implicated sleep duration (35) and depression (36) as risk factors for CVD. Another study of 385 292 UK biobank participants (37) reported that ~10% CVD events could be attributed to disturbed sleep. By contrast, a healthy sleep pattern reduced risk of CAD and stroke by 34%. A position paper of the European Society of Cardiology (ESC) working group on coronary pathophysiology and microcirculation (38) concluded that depression is associated with a 30% increased risk for future CAD events.
Low education, low income, and work stress are also considered as risk factors for CVD (39). In an analysis of a prospective cohort of 1.6 million Danish employees, Framke et al. (40) reported that low education was associated with higher risk of incident CVD and CVD mortality.

Over the last decade, large CVD outcome trials in patients with type-2 diabetes (T2D) have provided data on the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium glucose cotransporter 2 inhibitors (SGLT2i) to reduce cardio-renal events. Today’s awareness of the CVD continuum as a chain of pathophysiological events makes difficult to define risk in a binary manner using only primary and secondary prevention to drive management. Thus, the recent ESC guidelines on diabetes/prediabetes and CVD (2) recommend that patients with diabetes should be classified according to three levels of cardiovascular risk, into those at very high, high, or moderate risk (Figure 2).
The four available SGLT2 inhibitors have demonstrated to favourably affect a spectrum of CVD and kidney outcomes. Most recently, canagliflozin in the CREDENCE trial significantly reduced 3-point-MACE in a diabetes population with chronic kidney disease (CKD) (41). In DECLARE TIMI-58 trial, dapagliflozin vs. placebo did not significantly affect 3-point-MACE, possibly due to the lower-risk cohort recruited with ~60% of participants with only multiple risk factors without established ASCVD (42). The VERTIS CV trial with ertugliflozin also did not show a reduction in MACE, despite the fact that people with established ASCVD were studied (43). On the other hand, all the SGLT2 inhibitors investigated in the different trials showed a significant reduction in HF hospitalization. Most interestingly, dapagliflozin in DAPA-HF (44) and empagliflozin in EMPEROR-Reduced (45) showed a reduction in the combined endpoint of HF or CV death in patients with HFrEF with or without diabetes. A very recent meta-analysis representing the totality of CVD outcomes trial data for the four SGLT2 inhibitors available shows that reduction in risk for HF and CKD progression is the most consistent observation across the trials (46).

Despite using different definitions of renal endpoints, all SGLT2-inhibitor RCTs also showed protection against progression of diabetic kidney disease. In most trials, these findings were secondary endpoints, but CREDENCE demonstrated a significant 30% reduction in the primary composite endpoint of CKD, doubling of serum creatinine, death from kidney causes or CV death in people with diabetes and CKD (41).

A recent meta-analysis of RCTs concluded that also GLP-1 RAs lead to a significant reduction in the 3P-MACE as well as the risk of CV mortality, all-cause mortality, fatal and nonfatal stroke and heart failure hospitalization (47). Moreover, based on data from five GLP-1 RA CVD outcome trials, which enrolled patients both with and without ASCVD, there were no between-group differences in GLP-1 RAs benefit on 3P-MACE, indicating consistent protective effects in patients with established ASCVD, as well as in those with multiple risk factors. The results of these RCTs and meta-analyses support the ESC guidelines to prioritize the use of SGLT2i and GLP-1 RAs in patients with T2D at high/very high risk to prevent CVD and kidney complications (Figure 2).
Of note, an analysis of the ORIGIN trial data assessing the relationship between body weight and CVD outcomes reported findings that contradict conventional wisdom on body weight and health outcomes (48). In patients with DM/prediabetes, overweight/mild obesity was associated with lower all-cause and CV mortality compared to those with normal weight. Also, loss of weight related to higher all-cause and CV mortality compared to no weight loss, while weight gain was neutral. Further research is needed to clarify if recommendations on weight management should differentiate more clearly between moderate risk and patients with established ASCVD or elevated cardiovascular risk profiles.

The ESC in its 2020 publication on CVD statistics (49) described that in Europe the prevalence of major risk factors was higher in middle-income countries compared to high-income countries. In middle-income countries, the prevalence of hypertension was 23.8% compared with 15.7% in high-income countries. Prevention and control of arterial hypertension has then to be particularly intensive in middle-income countries. However, within the high-income countries after the improvement in hypertension awareness since the 1980s and 1990s, we have assisted to control figure rates with a plateau in the past decade (50). This finding is probably due to an inadequate accomplishment of guidelines leading to an improper management of elevated BP that could depend on a delayed start of BP management.
How can we improve the control of BP and cardiovascular risk? Probably, risk assessment should start before age 40 (51) due to the importance of early life exposure to risk factors and development of future CVD. The age of onset of hypertension correlates with CVD and mortality (52) and the BP trajectories exhibit sex differences that begin early and persist with aging, allowing the setting for later CVD (53). Thus, an early control of BP and other cardiovascular risk factors, particularly cholesterol, has to be performed to obtain an adequate prevention of CVD and renal disease.
A recent publication has opened a new door to delimitate the definition of normal BP to start intervention. Performed with data from the Multi-Ethnic Study of Atherosclerosis (54), the study (55) shows that beginning at a systolic BP (SBP) of 90 mmHg there is a progressive increase in coronary artery calcium and in ASCVD with progressing SBP. Hence, primordial prevention of BP elevation and other risk factors is necessary to improve cardiovascular prevention in subjects at risk of developing hypertension.
Intervention on BP at young ages is then needed and it must be considered that BP values will stay within the range of normalcy (SBP 90–129 mmHg) preventing the development of arterial hypertension in individuals with good cardiovascular health estimated as Life’s Simple 7 metrics (adequate values and performance of BMI, diet, smoking, physical activity, BP, cholesterol, and glucose) (56).
Treatment and control of hypertension in 2020 requires a substantial improvement and one of the ways to accomplish it and thus diminish the burden of disease consists in ensuring an adequate control of BP and the other main cardiovascular risk factors since the early stages of life.

New guidelines for the management of dyslipidemias from the ESC and the European Atherosclerosis Society have been published in 2020 (10). The treatment targets and goals for cardiovascular prevention defined in these guidelines are depicted in Table 1. The intensity of lipid-lowering treatment to accomplish approximate LDL-C targets relies on the use of moderate-intensity statin to reduce LDL-C by 30%, high-intensity statin (50% reduction), high-intensity statin plus ezetimibe (65% reduction), PCSK9 inhibitors (60% reduction), PCSK9 inhibitors plus high-intensity statin (75% reduction), and PCSK9 plus high-intensity statin plus ezetimibe (85% reduction).

Cardio-renal syndrome
There is a clear linkage between cardiovascular and renal diseases characterized by an elevated prevalence of CVD in patients with CKD, and vice versa. Accordingly, RCTs addressing new therapies with the capacity to improve CVD outcomes in patients with CKD are needed (62). Acute kidney injury, defined as an abrupt increase in serum creatinine, a fall in urinary volume, or both, is also a situation with relevant cardiovascular consequences mediated by cardiac inflammation and cellular apoptosis and necrosis rapidly developing and followed by cardiac fibrosis leading to CVD events, in particular HF (63). Like in the case of CKD trials new studies aimed to find therapies improving CVD and renal outcomes in acute kidney injury are required.
Usually patients are diagnosed as having CKD when they present with albuminuria and/or an estimated Glomerular filtration rate [GFR (eGFR)] <60 mL/min/1.73 m2. Detection of patients developing CKD before albuminuria develops or eGFR falls (early renal damage) actually is not clearly defined albeit some data indicate that certain interventions like control of adolescent hypertension can impede the future development of kidney failure (64).
On the other hand, the clinical diagnosis of progressive CKD is usually based on the evolution of eGFR and the variation in albuminuria and it is accepted that actual management for cardiovascular protection translates into renal protection (65), albeit CVD events, in particular HF, requiring hospitalization are associated with kidney failure independent of kidney risk factors (66).
The use of new antidiabetic drugs sodium glucose cotransporter 2 and inhibitors of glucagon-like peptide-1 in patients with diabetes and CKD has provided evidence of simultaneous cardio-renal protection (67). The results of similar trials using finerenone, a non-steroidal mineralocorticoid receptor antagonist, will be published soon (68).

COVID-19 and cardiovascular disease
The novel coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) initiated at the end of 2019. COVID-19 was shown initially to affect the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome. Later it was observed that it also affects multiple organs, including the cardiovascular system. Advanced age and male sex are accompanied by severe infection and mortality that is promoted by accompanying comorbidities, particularly CVD, hypertension, diabetes, obesity, CKD, chronic pulmonary disease, and cancer (69, 70). Ultimately, a severe prognosis is the consequence of endothelial dysfunction and COVID-19 is finally considered an endotheliopathy (71).
While waiting for adequate vaccines to prevent COVID-19 and specific medications counteracting the SARS-CoV-2, an array of medications, amply reviewed by Guzik et al. (72), has been considered for the treatment of COVID-19 patients with variable effects. It has been established that the use of renin–angiotensin–aldosterone antagonists for the treatment of hypertension and/or heart diseases could be beneficial for COVID-19 (73) as well as the use of anticoagulant therapy needed to diminish the risk of pulmonary embolism (74).
Cancer and cardiovascular disease
CVD and cancer continue to be the leading causes of death worldwide. Interestingly, CVD and cancer share common pathways (75, 76) and, in addition, an increasing number of cancer patients – successfully treated – show an increasing incidence of CVD mortality (77) and CVD events such as HF (78), ACS (79), and arrhythmia (80).

Future perspectives in preventive cardiology
Probably in the next years, new advances on precision medicine will appear with the help of more useful genetic tests and better characterization patients according to their metabolomics profile.

Summary and conclusions

The current article summarizes relevant advances on CVD prevention in 2020.
We have highlighted the need for different protocols for men and women because of differences in presenting symptoms of ACS among sex, the truly toxic effects of e-cigarettes, and the usefulness of intermittent fasting to reduce body weight, improve several chronic conditions and reverse aging. Four available SGLT2 inhibitors have demonstrated favourable effects on CVD and kidney outcomes. We have also underlined that CVD risk assessment should be started before age 40 given the importance of early life exposure to risk factors and development of future CVD events and that new treatment targets and goals have been defined in the new guidelines for the management of dyslipidemias.
Finally, despite the striking consequences of COVID-19 pandemic, prevention of most prevalent and relevant chronic diseases worldwide, CVD and cancer, should continue to be promoted by all actors (governments, scientific societies and mass media) at both population and individual levels. In this setting, an adequate and joint prevention program should be useful to fight both CVD and cancer. Let us get going!

Conflict of interest
R.E. reports grants from Cerveza y Salud, Spain, and Fundacion Dieta Mediterranea, Spain; also, personal fees for given lectures from Brewers of Europe, Belgium, Fundacion Cerveza y Salud, Spain, Pernaud-Ricard, Mexico, Instituto Cervantes, Alburquerque, USA; Instituto Cervantes, Milan, Italy; Instituto Cervantes, Tokyo, Japan; Lilly Laboratories, Spain; and Wine and Culinary International Forum, Spain, and non-financial support to organize a National Congress on Nutrition; and also, feeding trials with product from Grand Fountain and Uriach Laboratories, Spain. L.R. has been speaker and advisor for Astra-Zeneca, Bayer, Novartis, Medtronic, Pfizer, Vifor and Menarini. F.C. reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, personal fees from Mundipharma, personal fees from Novo Nordisk, personal fees from Pfizer, grants from King Gustav V and Queen Victoria Foundation, grants from Swedish Research Council, and grants from Swedish Heart & Lung Foundation, outside the submitted work. L.M.R. has nothing to declare.


1. Collet JP, Thiele H, Barbato E, et al. ESC Scientific Document Group. 2020 ESC Guidelines for the management of acute coronary syndromes in patient’s presenting without persistent ST-segment elevation. Eur Heart J 2020;

2. Cosentino F, Grant PJ, Aboyans V, et al. ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, prediabetes, and cardio-vascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41: 255–323.

3. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a re-port of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. JACC 2019; 74: e177-232–e232.

4. Lam CSP, Arnott C, Beale AL, Chandramouli C, Hilfiker-Kleiner D, Kaye DM, Ky B, Santema BT, Sliwa K, Voors AA. Sex differences in heart failure. Eur Heart J 2019; 40: 3859–3868.

5. Gili S, Cammann VL, Schlossbauer SA, et al. Cardiac arrest in Takotsubo syndrome: results from the Inter-TAK Registry. Eur Heart J 2019; 40: 2142–2151.

6. Lüscher TF. Sex and gender and cardiovascular medicine: impact in diabetes acute coronary syndromes and heart failure. Eur Heart J 2020; 41: 1311–1314.

7. Haider A, Bengs S, Luu J, et al. Sex and gender in cardiovascular medicine: presentation and outcomes of acute coronary syndrome. Eur Heart J 2020; 41: 1328–1336.

8. Blom MT, Oving I, Berdowski J, et al. Women have lower chances than men to be resuscitated and survive out-of-hospital cardiac arrest. Eur Heart J 2019; 40: 3824–3834.

9. Grundy SM. Does dietary cholesterol matter? Curr Atheroscler Rep 2016; 18: 68.

10. Mach F, Baigent C, Catapano AL, et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2020; 41: 111–188.

11. Helgadottir A, Thorleifsson G, Alexandersson KF, et al. Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease. Eur Heart J 2020; 41: 2618–2628.

12. Münzel T, Hahad O, Kuntic M, et al. Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes. Eur Heart J 2020; 41: 4057–4070.

13. Stanbrook MB, Drazen JM. Vaping-induced lung disease. A look forward by looking back. N Engl J Med 2020; 382: 1649–1650.

14. Kuntic M, Oelze M, Steven S, et al. Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2). Eur Heart J 2020; 41: 2472–2483.

15. Siedlinski M, Harrison DG, Guzik TJ. E-vaporating benefits of e-vaping. Eur Heart J 2020; 41: 2484–2486.

16. Estruch R, Ros E, Salas-Salvadó Jet al., PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 2018; 378: e34.

17. Li J, Guasch-Ferré M, Chung W, et al. The Mediterranean diet, plasma metabolome and cardiovascular disease risk. Eur Heart J 2020; 41: 2645–2656.

18. Tong TYN, Appleby PN, Key TJ, et al. The associations of major foods and fibre with risks of ischaemic and haemorrhagic stroke: a prospective study of 418 329 participants in the EPIC cohort across nine European countries. Eur Heart J 2020; 41: 2632–2640.

19. Vinchi F, Porto G, Simmelbauer A, et al. Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction. Eur Heart J 2020; 41: 2681–2695.

20. van der Wal HH, Grote Beverborg N, Dickstein K, et al. Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use. Eur Heart J 2019; 40: 3616–3625.

21. Voskoboinik A, Kalman JM, De Silva A, et al. Alcohol abstinence in drinkers with atrial fibrillation. N Engl J Med 2020; 382: 20–28.

22. 2018 Physical Activity Guidelines Advisory Committee. 2018 Physical Activity Guidelines Advisory Committee Scientific Report. Washington, DC: US Department of Health and Human Services; 2018.

23. Jeong SW, Kim SH, Kang Shet al. Mortality reduction with physical activity in patients with and without cardiovascular disease. Eur Heart J 2019; 40: 3547–3555.

24. Henriksson H, Henriksson P, Tynelius P, et al. Cardiorespiratory fitness, muscular strength, and obesity in adolescence and later chronic disability due to cardiovascular disease: a cohort study of 1 million men. Eur Heart J 2020; 41: 1503–1510.

25. Garnvik LE, Malmo V, Janszky I, et al. Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study. Eur Heart J 2020; 41: 1467–1475.

26. Elliott AD, Linz D, Mishima R, et al. Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort. Eur Heart J 2020; 41: 1479–1486.

27. Jenkin CR, Eime RM, Westerbeek H, O’Sullivan G, van Uffelen JGZ. Sport and ageing: a systematic review of the determinants and trend of participation in sport for older adults. BMC Public Health 2017; 17: 976.

28. Streese L, Khan AW, Deiseroth A, et al. High-intensity interval training modulates retinal microvascular phenotype and DNA methylation of p66Shc gene: a randomized con-trolled trial (EXAMIN AGE). Eur Heart J 2020; 41: 1514–1519.

29. Streese L, Khan AW, Deiseroth A, et al. Physical activity may drive healthy microvascular ageing via downregulation of p66Shc. Eur J Prev Cardiol 2020; 27: 168–176.

30. Estruch R, Ros E. Role of Mediterranean diet on weight loss and obesity-related diseases. Rev Endocr Metab Disord 2020; 21: 315–327.

31. Dale CE, Fatemifar G, Palmer TM, et al. Causal associations of adiposity and body fat distribution with coronary heart disease, stroke subtypes, and type 2 diabetes mellitus: a Mendelian randomization analysis. Circulation 2017; 135: 2373–2388.

32. Larsson SC, Ba¨ck M, Rees JMB, Mason AM, Burgess S. Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study. Eur Heart J 2020; 41: 221–226.

33. de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease. N Engl J Med 2019; 381: 2541–2255.

34. Moussa O, Ardissino M, Heaton Tet al. Effect of bariatric surgery on long-term cardiovascular outcomes: a nationwide nested cohort study. Eur Heart J 2020; 41: 2660–2667.

35. Wang C, Bangdiwala SI, Rangarajan S, et al. Association of estimated sleep duration and naps with mortality and cardiovascular events: a study of 116 632 people from 21 countries. Eur Heart J 2019; 40: 1620–1629.

36. Carney RM, Freedland KE. Depression and coronary heart disease. Nat Rev Cardiol 2017; 14: 145–155.

37. Fan M, Sun D, Zhou T, et al. Sleep patterns, genetic susceptibility, and incident cardiovascular disease: a prospective study of 385 292 UK biobank participants. Eur Heart J 2020; 41: 1182–1189.

38. Vaccarino V, Badimon L, Bremner JD, et al ESC Scientific Document Group Reviewers. Depression and coronary heart disease: 2018 position paper of the ESC working group on coronary pathophysiology and microcirculation. Eur Heart J 2020; 41: 1687–1696.

39. Tillmann T, Vaucher J, Okbay A, et al. Education and coronary heart disease: Mendelian randomisation study. BMJ 2017; 358: j3542.

40. Framke E, Sørensen JK, Andersen PK, et al. Contribution of income and job strain to the association between education and cardiovascular disease in 1.6 million Danish employees. Eur Heart J 2020; 41: 1164–1178.

41. Perkovic V, Jardine MJ, Neal B, et al. CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295–2306.

42. Wiviott SD, Raz I, Bonaca MP, et al. DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380: 347–357.

43. Cannon CP, Pratley R, Dagogo-Jack S, et al. McGuire DK for the VERTIS CV Investigators. Ertugliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2020; 383: 1425–1435.

44. McMurray JJV, Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995–2008.

45. Packer M, Anker SD, Butler J, et al. EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383: 1413–1424.

46. McGuire DK, Shih WJ, Cosentino F, et al. Sodium-glucose cotransporter 2 inhibitors, cardiovascular and kidney outcomes in patients with type 2 diabetes: a systematic review and meta-analysis of outcomes trials. JAMA Cardiol 2020;

47. Marsico F, Paolillo S, Gargiulo P, et al. Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials. Eur Heart J 2020; 41: 3346–3358.

48. Doehner W, Gerstein HC, Ried J, et al. Obesity and weight loss are inversely related to mortality and cardiovascular outcome in prediabetes and type 2 diabetes: data from the ORIGIN trial. Eur Heart J 2020; 41: 2668–2677.

49. Timmis A, Townsend N, Gale CP, et al European Society of Cardiology. European Society of Cardiology: cardiovascular disease statistics 2019. Eur Heart J 2020; 41: 12–85.

50. NCD Risk Factor Collaboration (NCD-RisC). Long-term and recent trends in hypertension awareness, treatment, and control in 12 high-income countries: an analysis of 123 nationally representative surveys. Lancet 2019; 394: 639–651.

51. Gidding SS, Robinson J. It is now time to focus on risk before age 40. J Am Coll Cardiol 2019; 74: 342–345.

52. Wang C, Yuan Y, Zheng M, et al. Association of age of onset of hypertension with cardiovascular diseases and mortality. J Am Coll Cardiol 2020; 75: 2921–2930.

53. Hongwei J, Kim A, Ebinger JE, et al. Sex differences in blood pressure trajectories over the life course. JAMA Cardiol 2020; 5: 19–26.

54. Bild DE, Bluemke DA, Burke GL, et al. Multiethnic study of atherosclerosis: objectives and design. Am J Epidemiol 2002; 156: 871–881.

55. Whelton SP, McEvoy JW, Shaw L, et al. Association of normal systolic blood pressure level with cardiovascular disease in the absence of risk factors. JAMA Cardiol 2020; 5: 1011–1018.

56. Plante TB, Koh I, Judd SE, et al. Life´s simple 7 and incident hypertension: the REGARDS study. J Am Heart Assoc 2020; 9: e016482.

57. Bhatt DL, Steg PG, Miller M, et al; for the REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Eng J Med 2019; 380: 11–22.

58. Boden WE, Bhatt DL, Toth PP, et al. Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidemia therapeutics. Eur Heart J 2020; 41: 2304–2312.

59. Poss AM, Holland WL, Summers SA. Risky lipids: refining the ceramide score that measures cardiovascular health. Eur Heart J 2020; 41: 381–382.

60. Ray KK, Phil M, Wright RS, et al; for the ORION-10 and ORION 11 Investigators. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020; 382: 1507–1519.

61. Raal FJ, Rosenson RS, Reeskamp LF, et al; for the Elipse HoFH Investigators. Evanicumab for homozygous familial hypercholesterolemia. N Eng J Med 2020; 383: 711–720.

62. Rossignol P, Agarwal R, Canaud B, et al. Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints. Eur Heart J 2019; 40: 880–886.

63. Legrand M, Rossignol P. Cardiovascular consequences of acute kidney injury. N Engl J Med 2020; 382: 2238–2247.

64. Leiba A, Fishman B, Twig G, et al. Association of adolescent hypertension with future end-stage renal disease. JAMA Intern Med 2019; 179: 517–523.

65. Ruiz-Hurtado G, Ruilope LM. Does cardiovascular protection translate into renal protection? Nat Rev Cardiol 2014; 11: 742–746.

66. Ishigami J, Cowan LT, Demmer RT, et al. Incident hospitalization with major cardiovascular diseases and subsequent risk of ESKD: implications for cardiorenal syndrome. J Am Soc Nephrol 2020; 31: 405–414.

67. Rangaswami J, Bhalla V, de Boer IH, et al; American Heart Association Council on the Kidney in Cardiovascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Lifestyle and Cardiometabolic Health. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation 2020; 142: e265–e286.

68. Bakris GL, Agarwal R, Anker SD, et al; on behalf of the FIDELIO-DKD Study Investigators. Design and baseline characteristics of the finerenone in reducing kidney failure and disease progression in diabetic kidney disease trial. Am J Nephrol 2019; 50: 333–344.

69. YangY, DingL, ZouX, et al.Visceraladi-posity and high intramuscular fat deposition independently predict critical illness in patients with SARS-CoV-2. Obesity 2020; 28: 2040–1002./oby.22971.

70. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020; 97: 829–838.

71. Libby P, Lüscher T, COVID-19 is, in the end, an endothelial disease. Eur Heart J 2020; 41: 4. 3038–3044.

72. Guzik TJ, Mohiddin SA, Dimarco A, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020; 116: 1666–1687.

73. Ruilope LM, Tamargo J, Ruiz-Hurtado G. Reni-angiotensin system inhibitors in the COVID-19 pandemic: consequences of antihypertensive drugs. Eur Heart J 2020; 41: 2067–2069.

74. Fauvel C, Weizman O, Trimaille A, et al; for the critical COVID-19 France Investigators. Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Eur Heart J 2020; 41: 3058–3068.

75. Vromman A, Ruvkun V, Shvartz E, et al. Stage-dependent differential effects of interleukin-1 isoforms on experimental atherosclerosis. Eur Heart J 2019; 40: 2482–2491.

76. P. Stage-dependent differential effects of interleukin-1 isoforms on experimental atherosclerosis. Eur Heart J 2019; 40: 2482–2491.

77. van’t Klooster CC, Ridker PM, Hjortnaes J, et al. The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study. Eur Heart J 2019; 40: 3901–3909.

78. Sturgeon KM, Deng L, Bluethmann Smet al. A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J 2019; 40: 3889–3897.

79. Potts JE, Iliescu CA, Lopez Mattei JC, et al. Percutaneous coronary intervention in cancer patients: a report of the prevalence and outcomes in the United States. Eur Heart J 2019; 40: 1790–1800.

80. Guha A, Dey AK, Jneid H, et al. Acute coronary syndromes in cancer patients. Eur Heart J 2019; 40: 1487–1490.

81. Zamorano JL, Lancellotti PR, Munoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 2768–2801.