Heart disease, stroke, peripheral arterial disease and ...lifestylemedicineeducation.org/wp-content/uploads/... · Peripheral Arterial Disease and Exercise NICE CG147 Exercise promotes

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Heart disease, stroke, peripheral arterial disease and exercise

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Learning objectives

1. Appreciate the burden of cardiovascular disease BHF, WHO

2. Understand the role of physical activity in the prevention and treatment of cardiovascular disease NICE Guidance CG68, CG94, CG108, CG147, CG162, CG172, CG181

3. Be able to provide safe and effective exercise advice to patients with heart disease, stroke or peripheral arterial disease

4. Know the contraindications to exercise in patients with cardiovascular disease BACPR

5. Understand the efficacy and cost effectiveness of cardiac rehabilitation programmes NICE CMG40

6. Make Every Contact Count NICE QS 84

WHO and

BHF Cardiovascular disease statistics 2015; Nation Institute for Clinical Excellence (NICE)WHO/WHF/WSO Global atlas on cardiovascular disease prevention and controlBritish Association for Cardiovascular prevention and rehabilitation

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Annual Cardiovascular Disease (CVD) Mortality

Stroke 39,000

deaths

41,000 premature

deaths

CHD 69,000

deaths

CHD single biggest cause of

death

28% of all UK

Deaths

BHF Cardiovascular disease statistics 2015WHO/WHF/WSO Global atlas on cardiovascular disease prevention and control 2011

UK World

NCD = Non Communicable DiseaseCHD = Coronary Heart Disease

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The role of physical inactivity in Cardiovascular Disease and associated costs

£11bn1.7

million hospital episodes

370 million prescriptions

Lee et al. Lancet 2012, Effect of physical inactivity on major NCDs BHF Cardiovascular disease statistics 2015; Centre for economic and business research 2014

Physical inactivity is directly responsible for a high proportion of CVD mortality in the UK and worldwide

% due to inactivity Coronary Heart Disease All-cause mortality

United Kingdom 11% 17%

World Average 6% 9%

Annual NHS CVD burdenBHF 2015, CEBR 2014

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Contractility ↑

Coronary blood flow ↑

Oxygen demand ↓

Stroke volume (SV) ↑

Heart rate (HR) ↓

Cardiovascular effects of exercise

Blood Pressure ↓Oxygen uptake ↑

Oxygen utilisation ↑Endothelial function ↑

Plasma volume ↑Blood viscosity↓

DURING exercise:SV ↑ initially, but most of the ↑ in cardiac output is reliant on ↑ HR

HR monitors are useful in moderate/vigorous, but not light activity

FYSS 21: Coronary artery diseaseWilson et al. Heart 2015: Basic Science behind the cardiovascular benefits of exercise

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Prevention of CVDRelationship with physical activity

Greatest health benefits NO physical activity SOME physical activity

Tanasescu et al. JAMA 2002: Exercise type and intensity in relation to coronary heart diseaseWoodcock et al. Int J Epi 2011: Non-vigorous physical activity and mortalityEuropean Guidelines 2012; Kyu et al. BMJ 2016 Analysis of the Global Burden of Disease studyDoH UK 2011: Start Active Stay Active; NICE CG68, CG94, CG172, CG181 Woodcock 2011, Kyu 2016

Physical activity

is beneficial in the primary

and secondary prevention of

all CVD

Mortalityin patients with

CVD

20-35% LOW HIGH

Physical activity level

1

0.5

0

Ad

just

ed r

elat

ive

risk

of

coro

nar

y h

ear

t d

isea

se

EACPR, NICE CG68, CG94, CG172, CG181

DoH 2011

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Prevention of CVD Direct benefits and risk reduction due to physical activity

Risk factor PAR Effects of physical activity

Smoking 36% Cessation adjunct

Abnormal lipids 49% ↓ triglyceride, total & LDL cholesterol

Hypertension 18% 30-50% risk reduction

Type 2 Diabetes 10% 30-40% risk reduction

Obesity 20% Weight maintenance

Psychosocial factors

33% 20-30% ↓ depression, anxiety & stress

Low fruit & veg 14% No direct effect of physical activity

Regular alcohol 7% No direct effect of physical activity

Physicalinactivity

12% Direct Benefit

WHO/WHF/WSO Global atlas on cardiovascular disease prevention and control Yusuf S,et al. Lancet 2004: INTERHEART study; DoH UK 2011: Start Active Stay Active Ussher et al. Cochrane 2014: Exercise interventions for smoking cessation AHA scientific statement 2003

PAR = Population Attributable Risk

Collectively,

these modifiable risk factors account for

90% of the risk of heart attack

worldwide

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Prevention of CVDAs good as medicines?

Network meta analysis of mortality outcomes in trials comparing drugs and exercise with controls

Favours intervention Favours control

Exercise is often as good as

medications in the secondary prevention of cardiovascular

disease

Naci & Ioannidis BMJ 2013: comparative effectiveness of exercise and drug interventions on mortality

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Coronary Artery Disease (CAD) and Exercise

Hambrecht et al. Circulation. 2004; PCI compared with exercise training; FYSS 21: Coronary artery diseaseWalther et al. Prev Cardio 2008: Regular exercise training compared with PCIACSM Position stand: Exercise and coronary artery disease; NICE CG94, CG172, CG181

88% with Exercise (£2328)

70% with PCI (£4722)

Exercise is

BETTER and CHEAPER than PCI for stable CAD

Exercise is indicated in the primary and secondary prevention of CAD

Patients with CAD should undertake baseline stress and fitness tests with ECG monitoring to assess risk and tailor exercise to current physical capacity

PCI = Percutaneous Coronary Intervention

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Heart Failure (HF) and exercise

All patients with chronic HF should be offered exercise-based rehabilitation

Meta-analysis showing effects of exercise in patients with heart failure

Hospitalisation

Quality of life &Exercise tolerance

Belardinelli et al JACC 2014: 10 yr exercise training in CHF; Piepoli et al. EJHF 2011: Exercise training in heart failureVan Tol et al EJHF 2006: Effects of exercise training in heart failureHagerman et al. IJC 2005: Hospitalisation in chronic heart failure; NICE CG108

HR=heart rateSBP=systolic blood

pressureCO=cardiac output VO2=peak oxygen

uptakeAT=anaerobic

threshold6-MWD=6-min

walking distanceMLWHFQ=Minnesota

Living with Heart Failure Questionnaire

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Stroke and Exercise NICE CG68

Vicious cycle

DeconditioningStroke

Variable Disability

Exercise intolerance

Increased Disability

Increased CVD risk

Reduced function

Reduced QOL

Improves walking & tolerance for ADLs

Exercise benefits

Naci & Ioannidis BMJ 2013: comparative effectiveness of exercise and drug interventions on mortalityNICE CG68; FYSS 47 Stroke; Stoller et al. BMC neurology: Effects of cardiovascular exercise after strokeSaunders et al. Cochrane 2013: Physical fitness training for stroke patients; ADLs Activities of Daily Living, QoL Quality of Life

Exercise significantly reduces mortality following stroke

Anticoagulants and Antiplatelets do NOT Naci, 2012

PersonaliseGoals

Reduces CVD risk directly

Improved QoL & Self-confidence

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Peripheral Arterial Disease and Exercise NICE CG147

Exercise promotes collateral blood flow, improves oxygen extraction and cardiovascular function in Peripheral Arterial Disease

Patients should exercise to the point of maximal pain

NICE CG147; Parmenter et al. Sports Med 2015: Exercise training for management of PADLane et al. Cochrane 2014: Exercise for intermittent claudication; FYSS 41 Peripheral arterial diseaseVemulapalli et al. 2015 Clin Cardiol network meta-analysis; Gupta & Elkins BJSM 2014: Walking training in intermittent claudication

Walking distanceWalking speed Perceived walking endurancePhysical activity levels

AmputationsFoot infectionsMortalityPain

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Cardiac Rehabilitation NICE CG108, CG172, CMG 40

Anderson & Taylor, Cochrane overview 2014: Cardiac rehabilitation; Lawler et al. AHJ 2011: Cardiac rehabilitation following MIACSM & AHA Joint position statement: Exercise and acute cardiovascular eventsBHF Cardiovascular disease statistics 2015; FYSS 21: Coronary artery disease; NICE CG108, CG172, CMG 40

~50% of all cardiac complications occur during the first month following a cardiac event FYSS 21

Therefore patients need assessment, screening and safe exercise prescription during this time ACSM

Cardiac rehabilitation is safe and effective and should start within 10 days of discharge from hospital NICE CG172

UK referral rates range from 13-88% with large inequalities and low heart failure access (2%)NICE CMG 40

Favours usual care

Favours cardiac

rehabilitation

Mortality ↓

Odds of dying

↓ 20%

Meta-analysis showing odds ratios for total mortality: exercise based cardiac rehabilitation versus usual care following MI Lawler 2011

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BUT…

Cardiac Rehabilitation

Overall mortality CVD mortality Re-infarction Hospital admissionsBP, lipids, disabilityTime off work

Only 14-43% uptake following MI Davies et al

Those most likely to benefit have lowest uptake Beswick et al 2005

Treatment for secondary prevention

Cost of adding 1 year to a

patients life

Aspirin/B-blocker <£1000

Cardiac rehab £1957

ACE inhibitor £3398

Statin £4246

CABG £3239-4601

PCI £3845-5889

Anderson & Taylor, Cochrane overview 2014: Cardiac rehabilitation; FYSS 21: Coronary artery disease; NICE CG108, CG172, CMG 40; Anderson et al. Cochrane 2016 Cardiac rehabilitation for CHD; ACSM & AHA Joint statement: Exercise and acute cardiovascular events; Lawler et al. AHJ 2011: Cardiac rehabilitation following MI; Heran et al. Cochrane; Exercise rehabilitation for patients with CHD; Fidan et al. QJM 2007:Economic analysis of treatments; Taylor et al. Cochrane 2014: Exercise rehabilitation for heart failure

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Considerations when exercising on medicines

Medication Exercise related pharmacology Patient implications

ß-blocker Maximum heart rate ↓Skeletal muscle blood flow ↓

↓ maximal exercise capacity↑ muscle fatigue

Diuretics ↑ salt loss (N.B. Hypokalaemia)↑urine output

↑ risk of dehydrationAvailability of toilets important

Calcium channel blocker

Negative chronotropes ↓ maximum capacity

ACE inhibitors No significant effects on exercise capacity

Digoxin ↑ contractility and stroke volume ↑ exercise capacity

Nitrates VasodilatationAnti-anginal

Risk of postural hypotensionCan be used prophylactically

Anticoagulants Risk of bleeding increased Tailor advice re: ↓ falls risk etc.

Statins No clear evidence supporting reduced performance or ↑ muscle pain

Caution in vigorous endurance sport

FYSS 21: Coronary artery diseaseParker et al. Circulation 2013: Effect of statins on skeletal muscle function

Medicines are not a contraindication to exercise

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Absolute Contraindications to Exercise in CVD

1. New or uncontrolled arrhythmia2. Resting or uncontrolled tachycardia3. Resting SBP >180mmHg or DBP

>100mmHg4. Symptomatic hypotension5. Unstable/ crescendo angina6. Acute or unstable heart failure7. Unstable diabetes8. Acute febrile illness

Adapted from British Association of Cardiac rehabilitation 2012ACSM position statement

Any patients with unstable or uncontrolled symptoms must be reviewed

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Safety Considerations in CVD patients

Exclude high-risk patients from vigorous activity

Screen high risk patients before exercise

• Recent cardiac event

• Heart failure, Recent/previous Stroke, PAD

• Re-screen anyone with unstable/uncontrolled symptoms

Stop exercise and promptly evaluate/refer if ANY of these symptoms (inform patients of these)

• chest pain or tightness

• dizziness or faintness

• pain in the arm or jaw

• severe shortness of breath

• an irregular heartbeat

• excessive fatigue

Adapted from British Association of Cardiac rehabilitation 2012; ACSM position statement; Thompson et al. Circulation 2007 : Exercise and acute cardiovascular events AHA statement

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• High intensity exercises carry a higher risk ACSM

• Warm up 15 minutes. Cool down 10 minutes • Avoid lying down until after cool down period• ICDs have a 10-30s delay between arrhythmia

and shock, so give safe exercise advice such as avoid swimming FYSS 30

• Avoid dehydration (increased risk of arrhythmia) FYSS 21

• Progression (duration & intensity) of exercise should be slow and gradual ACSM

• Stroke patients are 3x more likely to fall or suffer hip fractures so make the environment safe FYSS 47

• Good footwear and foot care are very important in PAD and/or type 2 diabetes

• Inactive individuals should start with a 2-3 month transition phase of light exercise only ACSM

Exercise Considerations in Cardiovascular Disease

ACSM Current comment: Exercise for persons with cardiovascular diseaseFYSS 21 Coronary artery disease; FYSS 30 Heart rhythm disturbanceFYSS 47 Stroke; ACSM 2015: Updated recommendations for Exercise Preparticipation Health Screening

Prescribing physical activity in daily practice for cardiovascular disease prevention using the acronym ACTIVE

Tina Varghese et al. Heart doi:10.1136/heartjnl-2015-308773 and Heart BMJ podcast

Copyright © BMJ Publishing Group Ltd & British Cardiovascular Society. All rights reserved.

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Weekly Physical Activity Recommendations

Sit Less

– excess sedentary behaviour causes death

Walk More

– walking is safe & effective

Tailor advice to the individual

American Heart Association; DoH UK 2011: Start Active Stay ActiveAdapted from British Association of Cardiac rehabilitation 2012Biddle et al. BMC 2016: Too much sitting and all-cause mortality

Refer these patients for

Cardiac Rehabilitation:

• Recent Myocardial Infarction• IHD/ Heart failure• Heart surgery/ Percutaneous

coronary intervention• Implantable Cardiac

Defibrillator

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Learning summary Heart disease, stroke, peripheral arterial disease and exercise

• Reassure your patientsExercise is safe following appropriate screening and assessment

• Educate your patientsUnstable/uncontrolled symptoms require clinical review

• Empower your patientsThe least active stand to gain the most

• Rehabilitate your patientsCARDIAC REHABILITATION saves lives, is effective, safe, cheap, underused and undervalued

• Exercise your patientsExercise can be as good as medicines

• Make Every Contact CountYOUR exercise advice can save lives

British Association of Cardiac Rehabilitation; ACSM position statementWoodcock et al. Int J Epi 2011: Non-vigorous physical activity and mortalityThompson et al. Circulation 2007 : Exercise and acute cardiovascular events AHA statementAnderson & Taylor, Cochrane overview 2014: Cardiac rehabilitation; NICE CMG 40 Naci 2013 Heart BMJ Podcast

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Supplement: A case study examplePre-participation Screening Summary of updated ACSM recommendations ACSM 2015

IntensityMedical

clearance required?

Known disease?

*Signs or Symptoms?

Regular Exerciser?

Yes

Yes Yes STOP

No

Yes No Mod

No No Mod/Vig

No

Yes Yes

No

Yes Yes

No No Light/Mod

ACSM 2015, Updated recommendations for Exercise Preparticipation Health Screening

DURING EXERCISEStop and promptly evaluate/refer if ANY of the above symptoms occur (inform patients of these)

*Active Signs & Symptomspain or discomfort in the chest, neck, jaw, arms; shortness of breath at rest or mild exertion; dizziness or syncope; orthopnoea or PND; ankle oedema; palpitations or tachycardia; intermittent claudication; known heart murmur; unusual fatigue or shortness of breath with usual activities

Q3Q2Q1

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Resources

• NICE Guidelines

• BACPR

• FYSS Physical activity in the prevention and treatment of disease

• ACSM Position Stands

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References

ACSM, 1994. ACSM Position stand: Exercise for Patients with Coronary Artery Disease. Med. Sci. Sports Exerc., 26(3), pp.i–iv.

ACSM, 1998. AHA/ACSM Joint Position Statement: Recommendations for Cardiovascular Screening, Staffing, and Emergency Policies at Health/Fitness Facilities. Medicine & Science in Sports & Exercise, 30(6).

AHA, 2015. American Heart Association. Available at: http://www.heart.org.

Anderson, L. & Taylor, R.S., 2014. Cardiac rehabilitation for people with heart disease: an overview of Cochrane systematic reviews. The Cochrane database of systematic reviews, 12, p.CD011273.

Anderson, L., Oldridge, N., Thompson, D. R., Zwisler, A.-D., Rees, K., Martin, N., & Taylor, R. S. (2016). Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease: Cochrane Systematic Review and Meta-Analysis. Journal of the American College of Cardiology, 67(1), 1–12.

Belardinelli, R. et al., 2012. 10-Year Exercise Training in Chronic Heart Failure. Journal of the American College of Cardiology, 60(16), pp.1521–1528.

Biddle, S. J. H., Bennie, J. A., Bauman, A. E., Chau, J. Y., Dunstan, D., Owen, N., … van Uffelen, J. G. Z. (2016). Too much sitting and all-cause mortality: is there a causal link? BMC Public Health, 16, 635.

Centre for Economic and Business Research (2014). The economic cost of cardiovascular disease from 2014-2020 in six European Economies. www.cebr.com/wp-content/ uploads/2015/08/Short-Report-18.08.14.pdf

DoH, 2011. Start Active , Stay Active. Strategy, p.62.

Eckel, R.H. et al., 2014. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 63(25 Pt B), pp.2960–84.

Fidan, D. et al., 2007. Economic analysis of treatments reducing coronary heart disease mortality in England and Wales, 2000-2010. QJM : monthly journal of the Association of Physicians, 100(5), pp.277–89.

Garber, C.E. et al., 2011. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: Guidance for prescribing exercise. Medicine and Science in Sports and Exercise, 43(7), pp.1334–1359.

Grimby, G. et al., 2011. 47. Stroke. In FYSS Physical Activity in the prevention and treatment of disease. pp. 611–621.

Gupta, S. & Elkins, M.R., 2014. Supervised walking training improves maximum and pain-free walking distances in people with intermittent claudication. British journal of sports medicine, 48(14), pp.1130–2.

Hagerman, I., Tyni-Lenné, R. & Gordon, A., 2005. Outcome of exercise training on the long-term burden of hospitalisation in patients with chronic heart failure. A retrospective study. International journal of cardiology, 98(3), pp.487–91.

Hambrecht, R. et al., 2004. Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: a randomized trial. Circulation, 109(11), pp.1371–8.

Heran, B.S. et al., 2011. Exercise-based cardiac rehabilitation for coronary heart disease. The Cochrane database of systematic reviews, (7), p.CD001800.

Kyu, H. H., Bachman, V. F., Alexander, L. T., Mumford, J. E., Afshin, A., Estep, K., … Forouzanfar, M. H. (2016). Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013. BMJ, 354(1), 869–82.

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References (cont.)

Lane, R. et al., 2014. Exercise for intermittent claudication. The Cochrane database of systematic reviews, 7, p.CD000990.

Lawler, P.R., Filion, K.B. & Eisenberg, M.J., 2011. Efficacy of exercise-based cardiac rehabilitation post-myocardial infarction: A systematic review and meta-analysis of randomized controlled trials. American Heart Journal, 162(4), pp.571–584.e2.

Manage, R.M., 2012. The BACPR Standards and Core Components for Cardiovascular Disease Prevention and Rehabilitation 2012.

Mendis, S., Puska, P. & Norrving, B., 2011. Global atlas on cardiovascular disease prevention and control. World Health Organization, pp.2–14.

Naci, H. & Ioannidis, J.P.A., 2013. Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. BMJ (Clinical research ed.), 347, p.f5577.

NICE, 2010a. CG 108 Chronic heart failure. NICE Guidelines.

NICE, 2012. CG 147 Lower limb peripheral arterial disease: diagnosis and management. NICE Guidelines, pp.1–30.

NICE, 2013a. CG 172 MI – secondary prevention care for patients following a myocardial. NICE Guidelines, (November).

NICE, 2008a. CG 68 Stroke and transient ischaemic attack. NICE Guidelines.

NICE, 2010b. CG 94 Unstable Angina and NSTEMI: The Early Management of Unstable Angina and Non-ST-Segment-Elevation Myocardial Infarction. NICE Guidelines, (November).

NICE, 2013b. CMG 40 Cardiac rehabilitation services. NICE Comissioning guides, (November 2013), pp.1–49.

NICE, 2008b. NICE CG 67 Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE Guidelines, 94(10), pp.1331–1332.

NICE, 2013c. NICE CG162 Stroke rehabilitation. NICE Guidelines.

NICE, 2015. QS 84 Physical activity : encouraging activity in all people in contact with the NHS. NICE quality standard, (March).

Parker, B.A. et al., 2013. Effect of statins on skeletal muscle function. Circulation, 127(1), pp.96–103.

Parker, B.A. & Thompson, P.D., 2012. Effect of statins on skeletal muscle: exercise, myopathy, and muscle outcomes. Exercise and sport sciences reviews, 40(4), pp.188–94.

Parmenter, B.J., Dieberg, G. & Smart, N.A., 2015. Exercise training for management of peripheral arterial disease: a systematic review and meta-analysis. Sports medicine (Auckland, N.Z.), 45(2), pp.231–44.

Piepoli, M.F. et al., 2011. Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation. European journal of heart failure, 13(4), pp.347–57.

Reibe, D., Franklin, B. A., Thompson, P. D., Garber, C. E., Whitefield, G. P., Magal, M., & Pesctello, L. S. (2015). Updating ACSM’s Recommendations for Exercise Preparticipation Health Screening. Medicine & Science in Sports & Exercise, 47(11), 2473–2479.

Saunders, D.H. et al., 2013. Physical fitness training for stroke patients. The Cochrane database of systematic reviews, 10, p.CD003316.

Sciences, C. et al., 2010. 30. Heart rhythm disturbances. FYSS.

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References (cont.)

Stahle, A. & Cider, A., 2010. 21. Coronary artery disease. In FYSS Physical Activity in the prevention and treatment of disease.

Stoller, O. et al., 2012. Effects of cardiovascular exercise early after stroke: systematic review and meta-analysis. BMC neurology, 12, p.45.

Tanasescu, M., 2002. Exercise Type and Intensity in Relation to Coronary Heart Disease in Men. JAMA, 288(16), p.1994.

Taylor, R.S. et al., 2014. Exercise-based rehabilitation for heart failure. The Cochrane database of systematic reviews, 4, p.CD003331.

Thompson, P.D. et al., 2007. Exercise and acute cardiovascular events placing the risks into perspective: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation, 115(17), pp.2358–68. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17468391 [Accessed March 27, 2015].

Thompson, P.D. et al., 2003. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical. Circulation, 107(24), pp.3109–16. Available at: http://circ.ahajournals.org/content/107/24/3109.full [Accessed January 27, 2015].

Van Tol, B.A.F. et al., 2006. Effects of exercise training on cardiac performance, exercise capacity and quality of life in patients with heart failure: a meta-analysis. European journal of heart failure, 8(8), pp.841–50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16713337 [Accessed February 25, 2015].

Townsend, N. et al., 2015. Cardiovascular Disease Statistics 2015, Available at: https://www.bhf.org.uk/publications/statistics/cvd-stats-2015

Ussher, M.H., Taylor, A.H. & Faulkner, G.E.J., 2014. Exercise interventions for smoking cessation. The Cochrane database of systematic reviews, 8, p.CD002295. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25170798 [Accessed February 26, 2015].

Vemulapalli, S., Dolor, R. J., Hasselblad, V., Subherwal, S., Schmit, K. M., Heidenfelder, B. L., … Schuyler Jones, W. (2015). Comparative Effectiveness of Medical Therapy, Supervised Exercise, and Revascularization for Patients With Intermittent Claudication: A Network Meta-analysis. Clinical Cardiology, 38(6), 378–86.

Walther, C. et al., 2008. Regular exercise training compared with percutaneous intervention leads to a reduction of inflammatory markers and cardiovascular events in patients with coronary artery disease. European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology, 15, pp.107–112.

Ward, C., 2010. 41 Peripheral arterial disease. In FYSS Physical Activity in the prevention and treatment of disease.

Wilson, M.G., Ellison, G.M. & Cable, N.T., 2015. Basic science behind the cardiovascular benefits of exercise. Heart, 101(10), pp.758–765. Available at: http://heart.bmj.com/content/101/10/758.long#ref-4 [Accessed April 28, 2015].

Woodcock, J. et al., 2011. Non-vigorous physical activity and all-cause mortality: Systematic review and meta-analysis of cohort studies. International Journal of Epidemiology, 40(July 2010), pp.121–138.

Yusuf, S. et al., 2004. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet, 364(9438), pp.937–52. Available at: http://www.sciencedirect.com/science/article/pii/S0140673604170189 [Accessed January 27, 2015].